Download Hi-Res ImageDownload to MS-PowerPointCite This:ACS Infect. Dis. 2019, 5, 10, 1718-1730

ArticleAugust 22, 2019

Modification at the 2′-Position of the 4,5-Series of 2-Deoxystreptamine Aminoglycoside Antibiotics To Resist Aminoglycoside Modifying Enzymes and Increase Ribosomal Target Selectivity
Click to copy article linkArticle link copied!

Girish C. Sati
Girish C. Sati
Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States
More by Girish C. Sati
Vikram A. Sarpe
Vikram A. Sarpe
Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States
More by Vikram A. Sarpe
http://orcid.org/0000-0001-9855-8923
Takayuki Furukawa
Takayuki Furukawa
Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States
More by Takayuki Furukawa
Sujit Mondal
Sujit Mondal
Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States
More by Sujit Mondal
Matilde Mantovani
Matilde Mantovani
Institute of Medical Microbiology, University of Zurich, 28 Gloriastrasse, 8006 Zürich, Switzerland
More by Matilde Mantovani
Sven N. Hobbie
Sven N. Hobbie
Institute of Medical Microbiology, University of Zurich, 28 Gloriastrasse, 8006 Zürich, Switzerland
More by Sven N. Hobbie
Andrea Vasella
Andrea Vasella
Organic Chemistry Laboratory, ETH Zürich, Vladimir-Prelog-Weg 1-5/10, 8093 Zürich, Switzerland
More by Andrea Vasella
Erik C. Böttger
Erik C. Böttger
Institute of Medical Microbiology, University of Zurich, 28 Gloriastrasse, 8006 Zürich, Switzerland
More by Erik C. Böttger
David Crich*
David Crich
Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States
*E-mail: [email protected]
More by David Crich
http://orcid.org/0000-0003-2400-0083

Open PDF Supporting Information (2)

ACS Infectious Diseases

Cite this: ACS Infect. Dis. 2019, 5, 10, 1718–1730

Click to copy citationCitation copied!

https://doi.org/10.1021/acsinfecdis.9b00128

Published August 22, 2019

Request reuse permissions

Abstract

Click to copy section linkSection link copied!

A series of derivatives of the 4,5-disubstituted class of 2-deoxystreptamine aminoglycoside antibiotics neomycin, paromomycin, and ribostamycin was prepared and assayed for (i) their ability to inhibit protein synthesis by bacterial ribosomes and by engineered bacterial ribosomes carrying eukaryotic decoding A sites, (ii) antibacterial activity against wild type Gram negative and positive pathogens, and (iii) overcoming resistance due to the presence of aminoacyl transferases acting at the 2′-position. The presence of five suitably positioned residual basic amino groups was found to be necessary for activity to be retained upon removal or alkylation of the 2′-position amine. As alkylation of the 2′-amino group overcomes the action of resistance determinants acting at that position and in addition results in increased selectivity for the prokaryotic over eukaryotic ribosomes, it constitutes an attractive modification for introduction into next generation aminoglycosides. In the neomycin series, the installation of small (formamide) or basic (glycinamide) amido groups on the 2′-amino group is tolerated.

Subjects

Keywords

The increasing threat of multidrug-resistant infectious diseases demands continued development of new and improved anti-infective agents. (1−6) In this regard, aminoglycosides (AGAs) (7−11) are strong candidates for further development because of their widespread availability, innate potency, and the extensive knowledge base covering their mechanism of action (10,12,13) and chemistry. (7,14−16) Together with the deep understanding of the mechanism of resistance, this knowledge base has long informed the structure-based design of new generations of AGAs, (17−24) as exemplified by the recent introduction of the semisynthetic AGA plazomicin 1 into clinical practice. (25,26) In addition to many aminoglycoside modifying enzymes (AMEs), (27−30) a second important and growing mechanism of AGA resistance is the modification of G1405 in the drug binding pocket in the decoding A site of the bacterial ribosome by the ribosomal methyl transferases (RMTs). (31) The action of the G1405 RMTs greatly diminishes the activity of all members of the 4,6-disubstituted 2-deoxystreptamine (DOS) class of AGAs, that is, all AGAs in current clinical use including plazomicin, (25,26,32) and is especially problematic when the responsible genes are encoded on the same plasmid as those for a metallocarbapenemase. (31,33−35) Fortunately, DOS-type AGAs lacking a ring substitution at the 6-position do not make direct contact with G1405 and are not susceptible to the action of RMTs. (36) Such AGAs include the 4,5-disubstituted DOS class such as paromomycin 2 and neomycin 3, and the unusual monosubstituted DOS AGA apramycin 4, (37−41) currently a clinical candidate for the treatment of complicated urinary tract infections. (42)

Accordingly, we have focused our efforts on the design and development of semisynthetic AGAs in the 4,5-DOS class with emphasis on modification at the 4′- and 6′-positions of paromomycin, (43−46) as exemplified by propylamycin 5 (4′-deoxy-4′-propylparomomycin). (47) In addition to thwarting the action of several AMEs, we discovered that the introduction of appropriate substituents to the 4′-position of paromomycin disproportionately reduces affinity for the drug binding site in the eukaryotic ribosomes, cytoplasmic and mitochondrial, thereby increasing target selectivity and reducing ototoxicity, an important side effect of AGA therapy, (48−50) as borne out by in vivo studies with guinea pigs. (44,47) Stimulated by early observations in the literature on the derivatization of the 2′-position of paromomycin and neomycin directed at circumventing the action of the AAC(2′) class of aminoglycoside acetyl transferase AMEs, (51−53) we now turn our attention to and report here on the possibility of circumventing AME action in conjunction with improvements in target selectivity by modification at the 2′-position of paromomycin 2, neomycin 3, and ribostamycin 6 (Figure 1).

Results

Click to copy section linkSection link copied!

Chemical Synthesis

By adapting a literature procedure for the regioselective tetra-N-acetylation of paromomycin, (51) treatment of a solution of paromomycin 2 and neomycin B 3 free bases in methanol containing 1N aqueous HCl with acetic anhydride gave 1,3,2′′′,6′′′-tetra-N-acetyl paromomycin 7 and 1,3,6′,2′′′,6′′′-penta-N-acetyl neomycin 8 as the major products in 41 and 39% isolated yields, respectively. Reductive amination of both 7 and 8 with benzaldehyde, followed by a second reductive amination with formaldehyde, and, in the case of the neomycin derivative by peracetylation, afforded the 2′-N-benzyl-2′-N-methyl paromomycin and neomycin derivatives 9 and 10 in 48 and 62% yield, respectively (Scheme 1). Reductive amination of 7 with acetaldehyde and propionaldehyde gave 11 and 12, whereas treatment of 8 with acetaldehyde and sodium cyanoborohydride gave 13, all in moderate to good yield. Hydrogenolysis of 9 and 10 over palladium hydroxide in methanol followed by heating to reflux with either aqueous sodium hydroxide or barium hydroxide and then Sephadex chromatography gave the 2′-N-methyl derivatives 14 and 15 of paromomycin and neomycin, respectively. Simple heating of 11–13 with aqueous sodium or barium hydroxide followed by Sephadex chromatography afforded the known (51) 2′-N-ethyl paromomycin derivative 16, the corresponding neomycin derivative 18, and the 2′-N-propyl paromomycin derivative 17. All compounds in this and subsequent schemes were isolated as their peracetate salts following lyophilization from aqueous acetic acid.

Scheme 1. Synthesis of 2′-N-Alkyl Derivatives of Paromomycin and Neomycin

Following the Farmitalia protocol, (52) installation of a benzyl carbamate on the amino group of 7 followed by peracetylation gave 19 in 57% yield. Hydrogenolysis of 19 followed by diazotization in aqueous acetic acid gave the known (52) pseudotrisaccharide 20 in 52% yield. Glycosylation of acceptor 20 with donors 21 and 22, prepared as described in the literature, (54,55) with activation by N-iodosuccinimide and trimethylsilyl triflate in a mixture of dichloromethane and dimethylformamide, so as to obtain the axial glycosides selectively, (56) gave 23 and 24 in 46 and 29% yield, respectively. Hydrogenolysis, heating to reflux in aqueous sodium hydroxide, and Sephadex chromatography then gave the 2′-desamino-2′-hydroxy paromomycin and neomycin derivatives 25 and 26, respectively (Scheme 2). Glycosylation with donor 21 leading directly to the glycoside 23 was considered preferable to the more elaborate sequence employed previously in the preparation of 25 from 20 by the Farmitalia group who nevertheless favored the use of DMF as solvent in their glycosylation reaction. (52) The cleavage of ring I from 19 by the nitrosylation protocol confirms the regioselectivity of the initial partial acetylation of 2 giving 7 (Scheme 1) and of all subsequent derivatives of it.

Scheme 2. Synthesis of 2′-Desamino-2′-hydroxy Paromomycin and Neomycin Derivatives

Formylation of 8 with formic acetic anhydride followed by acetylation gave the 2′-N-formyl neomycin derivative 27. This was converted by reaction with phosphorus oxychloride and triethylamine to the corresponding isocyanate, which without characterization was subject to the Barton deamination reaction (57−59) using tris(trimethylsilyl)silane (60) in place of the original tributyltin hydride, to afford the 2′-desamino derivative 28 in 44% yield for the two steps. Hydrolysis with hot barium hydroxide then afforded 29 in the standard manner (Scheme 3). No attempt was made to prepare the corresponding 2′-desamino paromomycin derivative in view of the modest antibacterial activity of the 2′-desamino-2′-hydroxy paromomycin derivative 25.

Scheme 3. Synthesis of 2′-Desamino Neomycin

Turning to the preparation of 2′-N-acyl derivatives, neomycin B 3 was treated with acetic anhydride in the presence of HCl to give crude 8, which was subjected to reaction with imidazole sulfonyl azide (61−64) and potassium carbonate in the presence of copper sulfate to give the corresponding 2′-azido derivative. Without isolation, and adopting the Grieco protocol for acetamide cleavage, (65) this compound was heated to reflux in tetrahydrofuran with Boc₂O and DMAP, followed by acetylation with acetic anhydride in pyridine to give 30 in 13% overall yield for the four steps from 3 (Scheme 4). Treatment with sodium methoxide in methanol followed by Staudinger reduction of the azide with trimethylphosphine (66) then afforded a 2′-amine 31 suitable for installation of various amides. Treatment of 31 with formic acetic anhydride or acetic anhydride in pyridine followed by aqueous methanolic sodium carbonate then gave amides 32 and 33 in 78 and 88% yield, respectively. Coupling of 31 with azidoacetic acid (67) by means of EDC and HOBt gave the azido acetamide 34 in 68% yield. Finally, stirring of 32 and 33 with wet trifluoroacetic acid in the presence of anisole, followed by sephadex chromatography and lyophilization from acetic acid gave the 2′-N-formamide 35, and an authentic sample of the acetamide 36 in 42, and 81% yields, respectively. In the case of the glycinamide 37, isolated in 48% yield, the removal of the carbamate groups was preceded by reduction of the azide (Scheme 4). It is of interest, although not inconsistent with the literature, (68−70) that the formamide 35 exists in D₂O solution as an unassigned 7:3 mixture of rotamers.

Scheme 4. Synthesis of Neomycin 2′-Amides

In the ribostamycin series, the parent 6 was regioselectively protected as the 1,3,6′-tris(benzyloxycarbamate) 38 by treatment with N-(benzyloxycarbonyloxy)-5-norborene-endo-2,3-dicarboximide (NBD) (71) in the presence of sodium carbonate in 36% yield. Sequential reductive amination with benzaldehyde and then with formaldehyde gave the 2′-N-benzyl-2′-N-methyl derivative 39 in 24% yield, while parallel treatment with acetaldehyde and sodium cyanoborohydride gave the 2′-N-ethyl derivative 40 in 44% yield. Hydrogenolysis of 39 and 40 over palladium hydroxide then afforded 2′-N-methyl and 2′-N-ethyl ribostamycin, 41 and 42, in 26 and 23% yield, respectively (Scheme 5). Reaction of 38 with formic acetic anhydride and pyridine provided the 2′-formamide 43 in 59%, which was converted to the peracetate 44 in 75% yield in the standard manner. Dehydration of 44 with phosphorusoxy chloride and triethylamine afforded the corresponding 2′-isonitrile, which was subjected to tris(trimethylsilyl)silane and AIBN in hot toluene to give the 2′-desamino derivative 45 in 66% yield for the two steps. Deprotection with sodium methoxide in methanol followed by hydrogenloysis then afforded 2′-desamino ribostamycin 46 in 61% yield.

Scheme 5. Synthesis of Ribostamycin Derivatives 41, 42, and 46

To prepare 2′-desamino-2′-hydroxy ribostamycin derivatives, we again took an approach based on glycosylation of a 2-deoxystreptamine derivative. Thus, adapting Hanessian’s protocol for the degradation of rings I and IV, (72) the perazido paromomycin derivative 47 (73) was treated with periodic acid followed by triethylamine to afford the 5-O-ribosyl-2-deoxystreptamine derivative 48 in 23% yield (Scheme 6). Installation of a trityl group on the primary alcohol to give 49 in 52% was followed by conversion of the cis-diol to the corresponding acetonide 50 in 95% yield with 2,2-dimethoxypropane under catalysis by camphor-10-sufonic acid. Treatment of 50 with tert-butyldimethylsilyl triflate in the presence of 2,6-lutidine gave a single monosilyl ether 51 in 82% yield. Notwithstanding the literature precedent for the regioselective monofunctionalization of 50-like diols at the 6-position, (74)51 was converted to the crystalline derivative 52 in 60% yield by Staudinger reduction of the azides followed by amide formation, whose structures were confirmed by X-ray crystallography (Supporting Information, Figure S1, CCDC 1908319). The glycosyl acceptor 51 was converted to the α-glycoside 55 in 47% yield by means of reaction with sulfoxide 53 (Supporting Information) on activation with triflic anhydride. Similarly, glycosylation of 51 with sulfoxide 54 (Supporting Information) gave the α-glycoside 56 in 65% yield. Treatment of 55 and 56 with tetrabutylammonium fluoride and then acetic acid affording the triols 57 and 58, both in 44% yield, was followed by Staudinger reaction and hydrogenolysis to give 2′-desamino-2′-hydroxy ribostamycin 59 and the ribostamycin regioisomer 60 in 51 and 40% yields, respectively (Scheme 6).

Figure 1. Some natural and semisynthetic aminoglycoside antibiotics.

Scheme 6. Synthesis of Ribostamycin Derivatives 59 and 60

Activity and Selectivity at the Target Level

All compounds were studied for their ability to inhibit protein synthesis in a series of cell-free translation assays as described previously. (43) These assays employed wild-type bacterial Mycobacterium smegmatis ribosomes and humanized hybrid M. smegmatis ribosomes carrying complete eukaryotic decoding A sites, that is, the crystallographically characterized drug binding pocket (Figure 3), (36,75) from human mitochondrial ribosomes (Mit 13), A1555G mutant mitochondrial ribosomes (A1555), and human cytoplasmic ribosomes (Cyt 14) (Figure 2 and Table 1). (76) This model system, developed in our laboratories, was previously employed to identify the mitoribosome as target in aminoglycoside ototoxicity, (77) to study the mechanisms of mutant rRNA-associated deafness, (78) and to rationalize aminoglycoside activity against protozoa. (79) In the series of experiments reported in Table 1, inhibition of the mitochondrial ribosome, together with slow clearance from the inner ear, is thought to be the root cause of AGA-induced ototoxicity; the hypersusceptibility to AGA-induced ototoxicity found in a subset of the population arises from the presence of the A1555G mutation in the mitochondrial decoding A site. (77,78,80,81) Inhibition of the human cytoplasmic ribosome on the other hand is expected to result in more systemic toxicity.

Figure 2. Decoding A sites of prokaryotic and eukaryotic ribosomes. The bacterial AGA binding pocket is boxed. The bacterial numbering scheme is illustrated for the AGA binding pocket. Changes from the bacterial ribosome binding pocket are colored green. The A1555G mutant conferring hypersusceptibility to AGA ototoxicity is colored red.

Table 1. Antiribosomal Activities (IC₅₀,μM) and Selectivities^a

	substituent			IC₅₀, μM				selectivity
compound	6′	2′	basic amino groups	bacterial	Mit13	A1555G	Cyt14	Mit13	A1555G	Cyt14
Neomycin Series
3	NH₂	NH₂	6	0.04	4.3	0.4	36	108	10	900
15	NH₂	NHMe	6	0.01	4.7	1.1	37	470	110	3700
18	NH₂	NHEt	6	0.02	11	1.6	43	550	80	2150
26	NH₂	OH	5	0.03	36	2.9	108	1200	97	3600
29	NH₂	H	5	0.03	22	0.9	85	773	30	2833
35	NH₂	NHCHO	5	0.12	54	13	127	450	108	1058
36	NH₂	NHAc	5	5.3	93	28	147	18	5.3	28
37	NH₂	NHglycyl	5	0.16	11	1.2	25	69	8	156
Paromomycin Series
2	OH	NH₂	5	0.04	142	12	31	3550	300	775
14	OH	NHMe	4	0.05	150	54	60	3000	1080	1200
16	OH	NHEt	5	0.05	220	84	43	4400	1680	860
17	OH	NHPr	5	0.07	223	58	32	3186	829	457
25	OH	OH	4	2.2	662	313	446	301	142	203
Ribostamycin Series
6	NH₂	NH₂	4	0.10
41	NH₂	NHMe	4	1.13
42	NH₂	NHEt		1.93
59	NH₂	OH	3	2.66
46	NH₂	H	3	9.93
60^b	NH₂	OH	4	>20

^{^a}

Selectivities are obtained by dividing the eukaryotic by the bacterial values.

^{^b}

Compound 60 is additionally modified at the 3′-position by replacement of the hydroxyl group by an amino group.

As shown in Table 1, 2′-N-methylation and ethylation have little to no effect on the ability of paromomycin or neomycin to inhibit translation by the bacterial ribosome. Even 2′-N-propylation has a minimal effect as demonstrated with the paromomycin derivative 17. The effects of these 2′-N-alkylations on translation by the mitochondrial and cytoplasmic hybrid ribosomes are minimal for paromomycin but result in significant increases in selectivity for neomycin. In addition, these modifications have a marked effect on A1555G mutant mitochondrial ribosomes resulting in increases in selectivity of between 3- and 10-fold. The minimal loss of inhibitory activity of 2′-N-ethyl paromomycin for the bacterial ribosome is consistent with the limited reduction in antibacterial activity observed previously for this modification. (51) In contrast to the minimal influence of 2′-N-alkylation in the paromomycin and neomycin series, the comparable 2′-N-alkylated ribostamycin derivatives 41 and 42 were found to be 10-fold less active than the parent against the bacterial ribosome. In view of the low antibacterioribosomal activity of 41 and 42 and all subsequent ribostamycin derivatives, the activity of ribostamycin compounds against the eukaryotic ribosomes was not investigated.

Substitution of a hydroxyl group for an amino group at the 2′-position has minimal influence on antiribosomal activity in the neomycin series (analogue 26), consistent with the antibacterial activity reported for this compound previously. (52) Notably, a significant increase in selectivity for all eukaryotic decoding sites (mitochondrial, A1555G, and cytosolic) is achieved by the 2′-hydroxyl modification. However, the identical substitution is detrimental for both paromomycin and ribostamycin as evidenced by the corresponding paromomycin and ribostamycin analogues 25 and 59. The high activity of 26 suggested that further such modifications would be tolerated in the neomycin series, as was borne out by the 2′-desamino neomycin derivative 29, which again displays increased across the board selectivity compared to the parent. The substantially reduced activity of 2′-desamino-2′-hydroxy paromomycin 25 and of 2′-desaminoribostamycin 46 discouraged us from making any further modifications to the 2′-position of paromomycin and ribostamycin that result in loss of the basic amine. In an attempt to remove the 2′-amino group without a change in the number of basic amines present, ribostamycin was converted to the regioisomer 60 in which the 2′-amino group has been substituted by an hydroxyl group, while the inverse modification was affected at the 3′-position. Unfortunately, this modification was associated with a substantial loss of activity.

Turning to the installation of amides at the 2′-position, and restricting ourselves to the neomycin series, formylation giving the neomycin derivative 35 resulted in little loss of activity against the bacterial ribosome coupled with a substantial increase in selectivity for the mitochondrial and mutant mitochondrial ribosomes. This is in contrast to 2′-N-acetylation, the modification introduced by the AAC(2′) family of AMEs, which led to a greater than 100-fold loss in activity in derivative 36. The negative influence of the 2′-N-acetyl modification on activity can be largely overcome by its coupling with the reinstallation of a basic amine as in the 2′-N-glycyl neomycin derivative 37, which shows only a 4-fold loss of activity against the bacterial ribosome compared to the parent. However, this modification comes with a substantial loss in selectivity with regard to the cytoplasmic ribosome. These observations on the influence of amide formation at the 2′-position are consistent with the prior literature describing other 2′-amides. Thus, it has been reported that the 2′-N-glycinamide derivatives of simple aminoalkyl 2,6-diamino-α-d-glucopyranosides, and of fortimicin B, retain antibacterial activity as does 2′-formamido sisomicin. (82−84)

Antibacterial Activity in the Absence and Presence of Aminoglycoside Modifying Enzymes

The antibacterial activities displayed by the various paromomycin, neomycin, and ribostamycin derivatives against clinical strains of the Gram-positive methicillin-resistant Staphylococcus aureus (MRSA) and the Gram-negative Escherichia coli (Table 2) were consistent with their ability to inhibit bacterial protein synthesis in the translation assays (Table 1). The more potent compounds were also screened for activity against a single wild-type clinical strain each of the ESKAPE pathogens, Klebsiella pneumoniae, Enterobacter cloacae, and Acinetobacter baumannii, with MICs determined to be ≤4 μg/mL (Table 2).

Table 2. Antibacterial Activities (MIC, μg/mL)^a

	substituent		MRSA	E. coli		K. pneu	E. cloa	A. baum
compound	6′	2′	AG038	AG001	AG003	AG215	AG290	AG225
Neomycin Series
3	NH₂	NH₂	0.5	1	1	0.25–0.5	1	1–2
15	NH₂	NHMe	0.5	2	1	0.5	0.5–1	1
18	NH₂	NHEt	0.5	1–2	1	0.5	0.5–1	1
26	NH₂	OH	2	2–4	2–4	0.5	1	1
29	NH₂	H	1	2	1–2	0.5	1	1
35	NH₂	NHCHO	2–4	4–8	4–8	1–2	2	2
36	NH₂	NHAc	>128	>128	>128
37	NH₂	NHglycyl	4	16	32
Paromomycin Series
2	OH	NH₂	4	2–4	4–8	1	2	2
16	OH	NHEt	8	16	16
14	OH	NHMe	8	8	16
17	OH	NHPr	8–16	16	16
25	OH	OH	64–128	>128	>128
Ribostamycin Series
6	NH₂	NH₂	4	4–8	4–8	2	4	4
41	NH₂	NHMe	64–128	64–128	64
42	NH₂	NHEt	>128	128	128
59	NH₂	OH	>128	>128	>128
46	NH₂	H	≥256
60^b	NH₂	OH	>128	>128	>128

^{^a}

All values were determined in duplicate using 2-fold dilution series.

^{^b}

Compound 60 is additionally modified at the 3′-position by replacement of the hydroxyl group by an amino group.

As the 2′-amino group is the target for acetylation by the AAC(2′) class of AMEs, the more active compounds were screened for activity against two clinical strains of E. coli carrying different isoforms of AAC(2′) (Table 3). The presence of either of these AAC(2′) isoforms greatly abrogates the activity of both paromomycin and neomycin, consistent with the minimal activity of authentic 2′-N-acetyl neomycin 36. In contrast, 2′-N-methylation, ethylation, and propylation, compounds 14–18, maintains activity in the presence of AAC(2′). Similarly, the 2′-desamino-2′-hydroxy and 2′-desamino modifications in the neomycin series, compounds 26 and 29, resist the AAC(2′) class of AMEs in E. coli, as does the 2′-N-formyl modification displayed in compound 35. Plazomicin, obtained by an improved synthesis, (32) and amikacin, one carrying a 2′-amino group and the other a 2′-hydroxy group, served as controls for the AAC(2′) AMEs in E. coli.

Table 3. Antibacterial Activities Against E. coli Strains with Acquired AAC(2′) Resistance and Mycobacteria with Intrinsic AAC(2′) Resistance (MIC, μg/mL)^a

	substituent		E. coli AG001	E. coli AG106	E. coli pH434	M. abscessus ATCC 19977 (AAC2′)	ratio M. abscessus wt/E. coli wt
compound	6′	2′	wt	AAC(2′)-1a	AAC(2′)-1b	wt
Neomycin Series
3	NH₂	NH₂	1	16	>64	16	16
15	NH₂	NHMe	2	2.0	2–4	0.25	0.125
18	NH₂	NHEt	1–2	1	2	0.25	0.125–0.25
26	NH₂	OH	2–4	2	4	2	0.5–1.0
29	NH₂	H	2	2	4	2	1
35	NH₂	NHCHO	4–8	8	8–16
37	NH₂	NHglycyl	16	16–32
Paromomycin Series
2	OH	NH₂	2–4	>64	>64	8	2–4
14	OH	NHMe	8	8	8	16	2
16	OH	NHEt	16		8	32	2
17	OH	NHPr	16		8	32	2
Ribostamycin Series
6	NH₂	NH₂	4–8	128	>128
plazomicin			0.5–1	8–16	8
amikacin (2′OH)			2	2	2

^{^a}

All values were determined in duplicate using 2-fold dilution series.

Mycobacterium abscessus is a growing threat in hospitalized patients with chronic pulmonary disease or cystic fibrosis. (85) The innate AGA susceptibility of M. abscessus is determined by the presence of a functional AAC(2′) AME, (86) prompting us to test the more active compounds against the M. abscessus reference strain ATCC 19977. To illustrate the effect of the mycobacterial AAC2′ on compound activity, we also calculated the ratio of M. abscessus wt (AAC2′ present) versus E. coli wt (no AAC2′ present). Inherently, the mycobacterial AAC2′ shows little activity toward paromomycin but significantly reduces the antimycobacterial activity of neomycin. In line with expectation, the 2′-N-alkyl derivatives of paromomycin 14, 16, and 17 did not show any difference compared to the parent; however, the same modifications in the neomycin series, as in compounds 15 and 18, were highly efficacious resulting in a 64-fold reduction in MIC values (Table 3). The 2′-desamino-2′-hydroxy and 2′-desamino derivatives 26 and 29 of neomycin also showed much greater activity against M. abscessus than the parent.

Finally, selected compounds were screened for activity in the presence of AAC(3), AAC(6′), ANT(4′,4′′), and APH(3′). As expected, none of the modifications investigated was effective at suppressing the activity of these AMEs.

Discussion

Click to copy section linkSection link copied!

Classically, the activity of AGAs is considered to be correlated to the number of basic amino groups (87) and so, following protonation at physiological pH, to the degree of electrostatic attraction with the negatively charged drug binding pocket. (88,89) The electrostatic component of the binding energy is supplemented by a number of direct and water-mediated hydrogen bonding contacts and other directional intermolecular noncovalent interactions between the drug and the binding pocket (Figure 3). (27,75,87,90−92) The partitioning of the contribution of an individual protonated amine to the binding energy between electrostatic and directed components necessarily varies with the location of the amine in the AGA. Thus, while the amines of rings I and II of the 4,5-AGAs are involved in multiple H-bonding interactions with the drug-binding pocket, those of ring IV do so to a lesser extent (Figure 3). Indeed, it has been suggested that ring IV serves simply as a concentration of positive charge that makes a strong electrostatic contribution to the binding energy. (93) Finally, intramolecular conformation-restricting noncovalent interactions within the body of the drug itself have also been suggested to be an important component of the binding energy. (94) Among the hydrogen bonding interactions between rings I and III of the 4,5-AGAs, specifically those between the protonated 2′-amino group and O4′′ or O5′′ of the ribofuranosyl moiety (Figure 3) (75,95) are featured prominently. On the basis of these interactions, Hermann and co-workers prepared the conformationally restricted paromomycin and neomycin analogues 61 and 62 and studied their binding to the bacterial decoding A site. (96,97) Contemporaneously, and with a view to exploiting the differing conformations of AGAs bound to the decoding A site and that of the ANT(4′,4′′) AMEs, Asensio and co-workers prepared 62 and the higher homologue 63. (98,99) Other workers have prepared complex aminoglycosides by ribofuranosylation of the 5-OH in the 4,6-AGAs to take advantage of this intramolecular interaction and other contacts. (100,101) Unfortunately, each of 61–63 showed reduced affinity for decoding A site models and reduced antibacterial activity, the latter in common with an earlier conformationally restricted analogue 64 of the ribostamycin isomer xylostacin. (102)

Figure 3. Schematic of the crystallographically determined interactions of neomycin 3 (X = NH₂⁺) and paromomycin 2 (X = O) with the AGA binding pocket. Ribostamycin 6 (X = NH₂⁺) binds identically but lacks ring IV.

The pattern of antibacterioribosomal activity (Table 1) and antibacterial activity (Table 2) of the present series of compounds, together with the reduced activity of 61–63, provides the opportunity to examine the interplay between electrostatic and hydrogen bonding interactions in greater detail. The parity in the ability of neomycin and its analogues 26 and 29 lacking the 2′-amino group to inhibit the function of the bacterial ribosome (Table 1) and the growth of wild-type Gram-negative pathogens (Table 2) indicates that the presence of five appropriately located protonated amino groups provides sufficient electrostatic attraction with the negatively charged ribosome to overcome the absence of the 2′-amino group for this scaffold. For paramomycin and ribostamycin on the other hand, with only five and four such basic amino groups, respectively, the reduction in the electrostatic component conferred by removal of the 2′-amino group is critical, as borne out by the reduced activity of 2′-desamino-2′-hydroxy paromomycin 25 with its four protonated amino groups and by the ribostamycin analogues 46 and 59, both with only three protonated amino groups (Tables 1 and 2). Compensating for the loss of C(2′)NH₂ in 59 by reintroducing an amino group at the 3′ position, resulting in compound 60, did not restore activity. This indicates that in the ribostamycin series, with only four basic amino groups, electrostatic attraction alone is not sufficient for activity but must be complemented by location of one of these groups at the 2′-position.

Alkylation of N2′ is tolerated when the molecule possesses five or more suitably placed basic amines as is clear from the activity of the neomycin and paromomycin analogs 14, 15, 16, 17, and 18 (Tables 1 and 3). The loss of activity observed for the 2′-N-alkylated ribostamycin analogues 41 and 42 on the other hand indicates that even the correct placement of four basic amino groups is insufficient to compensate for the destabilizing effect of the alkyl groups. The retention of activity of 14, 15, 16, 17, and 18 contrasts with the reduced activity of the cyclic (2′-N-alkylated) neomycin and paromomycin derivatives 61–63. Cyclization of the 2′-amine onto the 5′′-position was reported to result in a reduction in basicity of the 2′-amine in 61 and 62 by ∼1.5 pKa units. This reduction in pKa is most likely due to the inductively electron-withdrawing O4′′ ribosyl ring oxygen, which is β- to N2′ in 61 and 62, (103) albeit the authors suggested steric inhibition of solvation of the protonated amino group as the cause. (96,97,104) Whatever the underlying reason for the reduction in basicity, affinity for the ribosome was restored under more acidic conditions, illustrating the importance of protonation of N2′ in overcoming the negative effect of the cyclic modification. Simple alkylation, as in 14, 15, 16, 17, and 18, on the other hand is expected to increase the basicity of N2′ consistent with their high levels of activity. (103) The homologue 63 of 62 lacks the basicity-reducing vicinal relationship between N2′ and O4′′ present in 61 and 62 but also shows a significant reduction in antibacterial activity and affinity for a decoding A site model. (99) This suggests that the diminished activity of 61–63 is at least in part due to other factors such as the loss of a crystallographically observed (Figure 3) (75) hydrogen bond from 5′′–OH in the parent to N7 of G1491 at the bottom of the binding site. (96−99) Overall, in the absence of cyclic constraints, the presence of a basic amino group at the 2′-position of the 4,5-AGAs is not necessary provided five other appropriately located basic amino groups are present in the molecule. When a 4,5-series AGA contains only four basic amino groups, one of them must be at the 2′-position. Alkylation of the 2′-amino group is tolerated in the absence of cyclic constraints provided there are a minimum of five basic amino groups in the molecule.

With regard to the 2′-N-acyl derivatives of neomycin, the loss of activity observed with the acetamide 36 was anticipated in view of the well-known ability of the AAC(2′) AMEs to significantly reduce the activity of AGAs (Table 2). In view of the high levels of activity retained by neomycin derivatives 26 and 29, both of which lack a basic nitrogen at the 2′-position, the loss of activity due to 2′-acetamide formation cannot result from a reduction in electrostatic binding energy in neomycin. The loss of activity on acetamide formation can also not be due to the inclusion of a hydrophobic methyl group, as simple 2′-N-alkylation is well tolerated in both paromomycin and neomycin. By a process of elimination, the detrimental effect of the 2′-acetamido group in the neomycin series must arise either from a steric interaction or an unfavorable electrostatic interaction involving the amide carbonyl group. The steric component of this interaction is more important for the 2′-acetamide than for the 2′-N-alkyl derivatives because of the rigid nature of the amide function and its well-known orientation with respect to the pyranose ring in all 2-deoxy-2-acetamido glucopyranose derivatives. (69) Further, it results mainly from the presence of the acetamide methyl group as the corresponding formamide 36 is considerably more active. In addition to its smaller size, the formamide 36 is also capable of avoiding any unfavorable electrostatic interaction by population of the cis- rather than the trans-rotamer. (70) Finally, the unfavorable interaction in the acetamide is not so large as to prevent docking of the drug into the binding site, as it can be partially overcome by the introduction of a further basic amino group as in the glycinamide 37.

Conclusion

Click to copy section linkSection link copied!

Extensive structure activity relationships (SAR) have been provided, resulting from modification of the 2′-position by deletion, replacement by a hydroxy group, alkylation, and in part acylation of the AGAs neomycin, paromomycin, and ribostamycin. This SAR leads to a series of conclusions on the influence of modification at this position on ribosomal affinity and antibacterial activity. Thus, the presence of a basic amino group at the 2′-position of the 4,5-AGAs is not essential for activity provided five other suitably placed basic amines are present in the molecule. In contrast, a basic amino group is required at the 2′-position when a 4,5-series AGA contains only four such basic amines. With five correctly placed basic amino groups present, alkylation of the 2′-amine is tolerated. Most notably, in paromomycin and in particular neomycin modification of the 2′-amino group also results in a gain in selectivity for the bacterial over the eukaryotic ribosomes, thereby providing an attractive means of both overcoming resistance due to the presence of AAC(2′)-type resistance determinants and increasing ribosomal target selectivity by a single modification.

Finally, the changes in selectivity between the prokaryotic and the different eukaryotic ribosomes occasioned by the various modifications introduced at the 2′-position (Table 1) presumably arise by indirect effects as the 2′-amine makes no direct contact with the drug binding pocket (Figure 3). These differential effects likely arise from interactions of the AGAs with the ribosomal base 1491, which is G in the bacterial ribosomes and A or C in the humanized ribosomes (Figure 2). Thus, modification of the 2′-substituent necessarily affects the CH−π interaction of the 4′–C–H bond with the base 1491 and, because of the H-bond network, the H-bond of the 5′′-hydroxyl group with the same base (Figure 3), both in a base-dependent manner.

Supporting Information

Click to copy section linkSection link copied!

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsinfecdis.9b00128.

Full experimental details and copies of ¹H and ¹³C NMR spectra for all new AGAs (PDF)
Crystallographic data (CIF)

Terms & Conditions

Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Author Information

Click to copy section linkSection link copied!

Corresponding Author
- David Crich - Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States; Present Address: D.C.: Departments of Pharmaceutical and Biomedical Sciences, and Chemistry, and Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, United States; http://orcid.org/0000-0003-2400-0083; Email: [email protected]
Authors
- Girish C. Sati - Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States
- Vikram A. Sarpe - Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States; Present Address: V.A.S.: Department of Pharmaceutical and Biomedical Sciences, and Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, United States; http://orcid.org/0000-0001-9855-8923
- Takayuki Furukawa - Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States
- Sujit Mondal - Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States
- Matilde Mantovani - Institute of Medical Microbiology, University of Zurich, 28 Gloriastrasse, 8006 Zürich, Switzerland
- Sven N. Hobbie - Institute of Medical Microbiology, University of Zurich, 28 Gloriastrasse, 8006 Zürich, Switzerland
- Andrea Vasella - Organic Chemistry Laboratory, ETH Zürich, Vladimir-Prelog-Weg 1-5/10, 8093 Zürich, Switzerland
- Erik C. Böttger - Institute of Medical Microbiology, University of Zurich, 28 Gloriastrasse, 8006 Zürich, Switzerland
Notes
The authors declare the following competing financial interest(s): D.C., A.V., S.N.H., and E.C.B. are cofounders of and have an equity interest in Juvabis AG, a biotech startup operating in the field of aminoglycoside antibiotics.

Acknowledgments

Click to copy section linkSection link copied!

We thank the NIH (AI123352) for support and Dr. Philip Martin, WSU, for the X-ray structure. E.C.B. thanks the Swiss National Science Foundation (SNF No. 407240_166998) and JPIAMR “RIBOTARGET” (SNF No. 40AR40_185777) for partial support of the work in Zurich.

References

Click to copy section linkSection link copied!

This article references 104 other publications.

1
Chang, H.-H., Cohen, T., Grad, Y. H., Hanage, W. P., O’Brien, T. F., and Lipsitch, M. (2015) Origin and Proliferation of Multiple-Drug Resistance in Bacterial Pathogens. Microbiol. Mol. Biol. Rev. 79, 101– 116, DOI: 10.1128/MMBR.00039-14
Google Scholar
1
Origin and proliferation of multiple-drug resistance in bacterial pathogens
Chang, Hsiao-Han; Cohen, Ted; Grad, Yonatan H.; Hanage, William P.; O'Brien, Thomas F.; Lipsitch, Marc
Microbiology and Molecular Biology Reviews (2015), 79 (1), 101-116CODEN: MMBRF7; ISSN:1098-5557. (American Society for Microbiology)
Many studies report the high prevalence of multiply drug-resistant (MDR) strains. Because MDR infections are often significantly harder and more expensive to treat, they represent a growing public health threat. However, for different pathogens, different underlying mechanisms are traditionally used to explain these observations, and it is unclear whether each bacterial taxon has its own mechanism(s) for multidrug resistance or whether there are common mechanisms between distantly related pathogens. In this review, we provide a systematic overview of the causes of the excess of MDR infections and define testable predictions made by each hypothetical mechanism, including exptl., epidemiol., population genomic, and other tests of these hypotheses. Better understanding the cause(s) of the excess of MDR is the first step to rational design of more effective interventions to prevent the origin and/or proliferation of MDR.
2
Fisher, J. F. and Mobashery, S. (2016) Endless Resistance. Endless Antibiotics?. MedChemComm 7, 37– 49, DOI: 10.1039/C5MD00394F
Google Scholar
2
Endless resistance. Endless antibiotics?
Fisher, Jed F.; Mobashery, Shahriar
MedChemComm (2016), 7 (1), 37-49CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
The practice of medicine was profoundly transformed by the introduction of the antibiotics (compds. isolated from Nature) and the antibacterials (compds. prepd. by synthesis) for the control of bacterial infection. As a result of the extraordinary success of these compds. over decades of time, a timeless biol. activity for these compds. has been presumed. This presumption is no longer. The inexorable acquisition of resistance mechanisms by bacteria is retransforming medical practice. Credible answers to this dilemma are far better recognized than they are being implemented. In this perspective we examine (and in key respects, reiterate) the chem. and biol. strategies being used to address the challenge of bacterial resistance.
3
Pendleton, J. N., Gorman, S. P., and Gilmore, B. F. (2013) Clinical Relevance of ESKAPE Pathogens. Expert Rev. Anti-Infect. Ther. 11, 297– 308, DOI: 10.1586/eri.13.12
Google Scholar
3
Clinical relevance of the ESKAPE pathogens
Pendleton, Jack N.; Gorman, Sean P.; Gilmore, Brendan F.
Expert Review of Anti-Infective Therapy (2013), 11 (3), 297-308CODEN: ERATCK; ISSN:1478-7210. (Expert Reviews Ltd.)
A review. In recent years, the Infectious Diseases Society of America has highlighted a faction of antibiotic-resistant bacteria (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) - acronymically dubbed the ESKAPE pathogens' - capable of escaping' the biocidal action of antibiotics and mutually representing new paradigms in pathogenesis, transmission and resistance. This review aims to consolidate clin. relevant background information on the ESKAPE pathogens and provide a contemporary summary of bacterial resistance, alongside pertinent microbiol. considerations necessary to face the mounting threat of antimicrobial resistance.
4
O'Connell, K. M. G., Hodgkinson, J. T., Sore, H. F., Welch, M., Salmond, G. P. C., and Spring, D. R. (2013) Combating Multidrug-Resistant Bacteria: Current Strategies for the Discovery of Novel Antibacterials. Angew. Chem., Int. Ed. 52, 10706– 10733, DOI: 10.1002/anie.201209979
Google Scholar
4
Combating Multidrug-Resistant Bacteria: Current Strategies for the Discovery of Novel Antibacterials
O'Connell, Kieron M. G.; Hodgkinson, James T.; Sore, Hannah F.; Welch, Martin; Salmond, George P. C.; Spring, David R.
Angewandte Chemie, International Edition (2013), 52 (41), 10706-10733CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. The introduction of effective antibacterial therapies for infectious diseases in the mid-20th century completely revolutionized clin. practices and helped to facilitate the development of modern medicine. Many potentially life-threatening conditions became easily curable, greatly reducing the incidence of death or disability resulting from bacterial infections. This overwhelming historical success makes it very difficult to imagine life without effective antibacterials; however, the inexorable rise of antibiotic resistance has made this a very real and disturbing possibility for some infections. The ruthless selection for resistant bacteria, coupled with insufficient investment in antibacterial research, has led to a steady decline in the efficacy of existing therapies and a paucity of novel structural classes with which to replace them, or complement their use. This situation has resulted in a very pressing need for the discovery of novel antibiotics and treatment strategies, the development of which is likely to be a key challenge to 21st century medicinal chem.
5
Wright, G. D. (2015) Solving the Antibiotic Crisis. ACS Infect. Dis. 1, 80– 84, DOI: 10.1021/id500052s
Google Scholar
5
Solving the Antibiotic Crisis
Wright, Gerard D.
ACS Infectious Diseases (2015), 1 (2), 80-84CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)
A review. Antibiotics are essential for both treating and preventing infectious diseases. Paradoxically, despite their importance as pillars of modern medicine, we are in danger of losing antibiotics because of the evolution and dissemination of resistance mechanisms throughout all pathogenic microbes. This fact, coupled with an inability to bring new drugs to market at a pace that matches resistance, has resulted in a crisis of global proportion. Solving this crisis requires the actions of many stakeholders, but chemists, chem. biologists, and microbiologists must drive the scientific innovation that is required to maintain our antibiotic arsenal. This innovation requires (1) a deep understanding of the evolution and reservoirs of resistance; (2) full knowledge of the mol. mechanisms of antibiotic action and resistance; (3) the discovery of chem. and genetic probes of antibiotic action and resistance; (4) the integration of systems biol. into antibiotic discovery; and (5) the discovery of new antimicrobial chem. matter. Addressing these pressing scientific gaps will ensure that we can meet the antibiotic crisis with creativity and purpose.
6
Wright, P. M., Seiple, I. B., and Myers, A. G. (2014) The Evolving Role of Chemical Synthesis in Antibacterial Drug Discovery. Angew. Chem., Int. Ed. 53, 8840– 8863, DOI: 10.1002/anie.201310843
Google Scholar
6
The Evolving Role of Chemical Synthesis in Antibacterial Drug Discovery
Wright, Peter M.; Seiple, Ian B.; Myers, Andrew G.
Angewandte Chemie, International Edition (2014), 53 (34), 8840-8869CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. The discovery and implementation of antibiotics in the early twentieth century transformed human health and wellbeing. Chem. synthesis enabled the development of the first antibacterial substances, organoarsenicals and sulfa drugs, but these were soon outshone by a host of more powerful and vastly more complex antibiotics from nature: penicillin, streptomycin, tetracycline, and erythromycin, among others. These primary defences are now significantly less effective as an unavoidable consequence of rapid evolution of resistance within pathogenic bacteria, made worse by widespread misuse of antibiotics. For decades medicinal chemists replenished the arsenal of antibiotics by semisynthetic and to a lesser degree fully synthetic routes, but economic factors have led to a subsidence of this effort, which places society on the precipice of a disaster. We believe that the strategic application of modern chem. synthesis to antibacterial drug discovery must play a crit. role if a crisis of global proportions is to be averted.
7
Umezawa, S. (1974) Structures and Syntheses of Aminoglycoside Antibiotics. Adv. Carbohydr. Chem. Biochem. 30, 111– 182, DOI: 10.1016/S0065-2318(08)60264-4
Google Scholar
7
Structures and syntheses of aminoglycoside antibiotics
Umezawa, Sumio
Advances in Carbohydrate Chemistry and Biochemistry (1974), 30 (), 111-82CODEN: ACBYAP; ISSN:0065-2318.
A review with 254 refs. on structures, synthesis and chem. modifications of aminoglycoside antibiotics.
8
Haddad, J., Kotra, L. P., and Mobashery, S. (2001) in Glycochemsitry: Principles, Synthesis, and Applications (Wang, P. G., and Bertozzi, C. R., Eds.) pp 307– 351, Dekker, New York.
Google Scholar
There is no corresponding record for this reference.
9
Vakulenko, S. B. and Mobashery, S. (2003) Versatility of Aminoglycosides and Prospects for Their Future. Clin. Microbiol. Rev. 16, 430– 450, DOI: 10.1128/CMR.16.3.430-450.2003
Google Scholar
9
Versatility of aminoglycosides and prospects for their future
Vakulenko, Sergei B.; Mobashery, Shahriar
Clinical Microbiology Reviews (2003), 16 (3), 430-450CODEN: CMIREX; ISSN:0893-8512. (American Society for Microbiology)
A review. Aminoglycoside antibiotics have had a major impact on our ability to treat bacterial infections for the past half century. Whereas the interest in these versatile antibiotics continues to be high, their clin. utility has been compromised by widespread instances of resistance. The multitude of mechanisms of resistance is disconcerting but also illuminates how Nature can manifest resistance when bacteria are confronted by antibiotics. This article reviews the most recent knowledge about the mechanisms of aminoglycoside action and the mechanisms of resistance to these antibiotics.
10
(2007) Aminoglycoside Antibiotics: From Chemical Biology to Drug Discovery (Arya, D. P., Ed.) Wiley, Hoboken, NJ.
Google Scholar
There is no corresponding record for this reference.
11
Jackson, J., Chen, C., and Buising, K. (2013) Aminoglycosides: How Should We Use Them in the 21st Century?. Curr. Opin. Infect. Dis. 26, 516– 525, DOI: 10.1097/QCO.0000000000000012
Google Scholar
11
Aminoglycosides: how should we use them in the 21st century?
Jackson, Justin; Chen, Caroline; Buising, Kirsty
Current Opinion in Infectious Diseases (2013), 26 (6), 516-525CODEN: COIDE5; ISSN:0951-7375. (Lippincott Williams & Wilkins)
Purpose of review: Aminoglycoside antibiotics (AGAs) have proved an invaluable part of our antimicrobial armamentarium since their introduction into practice over 60 years ago. This review summarizes recent developments, defining their role in the context of the current global epidemic of antibiotic resistance, raising awareness of their toxicity profile, and highlighting current data on their utility as synergistic agents. Recent findings: Clinicians are facing an unprecedented threat from antibiotic resistance, resulting in an increased reliance on the addn. of an AGA to provide adequate empirical cover in cases of severe sepsis. Concurrently, an increased awareness of the potential for severe disability, particularly from vestibular toxicity, has restrained directed therapy of AGAs to situations in which there are no appropriate alternatives. Their role as synergistic agents in the treatment of enterococcal endocarditis is currently under reevaluation, and new data have emerged on combination therapy for Pseudomonas aeruginosa bacteremia. AGAs are themselves coming under increasing threat from resistance, predominately from aminoglycoside modifying enzymes (mediating selective resistance) and 16S rRNA methyltransferases (conferring class-wide resistance). New agents and the development of alternate ways to circumvent resistance are likely to have important roles in future clin. care. Summary: Aminoglycosides retain an invaluable but well defined role, and will remain important agents into the foreseeable future.
12
Vicens, Q. and Westhof, E. (2003) RNA as a Drug Target: The Case of Aminoglycosides. ChemBioChem 4, 1018– 1023, DOI: 10.1002/cbic.200300684
Google Scholar
12
RNA as a drug target: The case of aminoglycosides
Vicens, Quentin; Westhof, Eric
ChemBioChem (2003), 4 (10), 1018-1023CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review discusses the interactions between aminoglycosides and the 16S rRNA, as well as the challenges small mols. must face to target RNA. It describes the mol. recognition between rRNA and aminoglycosides as well as the mechanism of action of aminoglycoside antibiotics. It discusses how strategies aimed at overcoming resistance due to RNA modifications or mutations need to cope with toxicity. The advantages of targeting RNA mol. switches, whose occurrence is now revealed in various RNA mols., are also considered.
13
Kondo, J., and Westhof, E. (2014) in Antibioitcs: Targets, Mechanisms and Resistance (Gualerzi, C. O., Brandi, L., Fabbretti, A., and Pon, C. L., Eds.) pp 453– 470, Wiley-VCH, Weinheim.
Google Scholar
There is no corresponding record for this reference.
14
Haddad, J., Liu, M.-Z., and Mobashery, S. (2001) in Glycochemistry: Principles, Synthesis, and Applications (Wang, P. G., and Bertozzi, C. R., Eds.) pp 353– 424, Dekker, New York.
Google Scholar
There is no corresponding record for this reference.
15
Wang, J., and Chang, C.-W. T. (2007) in Aminoglycoside Antibiotics (Arya, D. P., Ed.) pp 141– 180, Wiley, Hoboken, NJ.
Google Scholar
There is no corresponding record for this reference.
16
Berkov-Zrihen, Y., and Fridman, M. (2014) in Modern Synthetic Methods in Carbohydrate Chemistry; From Monosaccharides to Complex Glycoconjugates (Werz, D. B., and Vidal, S., Eds.) pp 161– 190, Wiley, Weinheim.
Google Scholar
There is no corresponding record for this reference.
17
Price, K. E., Godfrey, J. C., and Kawaguchi, H. (1974) Effect of Structural Modifications on the Biological Properties of Aminoglycoside Antibiotics Containing 2-Deoxystreptamine. Adv. Appl. Microbiol. 18, 191– 307, DOI: 10.1016/S0065-2164(08)70572-0
Google Scholar
17
Effect of structural modifications on the biological properties of aminoglycoside antibiotics containing 2-deoxystreptamine
Price K E; Godfrey J C
Advances in applied microbiology (1974), 18 (0), 191-307 ISSN:0065-2164.
There is no expanded citation for this reference.
18
Becker, B. and Cooper, M. A. (2013) Aminoglycoside Antibiotics in the 21st Century. ACS Chem. Biol. 8, 105– 115, DOI: 10.1021/cb3005116
Google Scholar
18
Aminoglycoside Antibiotics in the 21st Century
Becker, Bernd; Cooper, Matthew A.
ACS Chemical Biology (2013), 8 (1), 105-115CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
A review. Aminoglycoside antibiotics were among the first antibiotics discovered and used clin. Although they have never completely fallen out of favor, their importance has waned due to the emergence of other broad-spectrum antibiotics with fewer side effects. Today, with the dramatically increasing rate of infections caused by multidrug-resistant bacteria, focus has returned to aminoglycoside antibiotics as one of the few remaining treatment options, particularly for Gram-neg. pathogens. Although the mechanisms of resistance are reasonably well understood, our knowledge about the mode of action of aminoglycosides is still far from comprehensive. In the face of emerging bacterial infections that are virtually untreatable, it is time to have a fresh look at this old class to reinvigorate the struggle against multidrug-resistant pathogens.
19
Yang, L. and Ye, X. S. (2010) Development of Aminoglycoside Antibiotics Effective Against Resistant Bacterial Strains. Curr. Top. Med. Chem. 10, 1898– 1926, DOI: 10.2174/156802610793176684
Google Scholar
19
Development of aminoglycoside antibiotics effective against resistant bacterial strains
Yang, Lin; Ye, Xin-Shan
Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2010), 10 (18), 1898-1926CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)
A review. Aminoglycosides are important broad-spectrum antibiotics used in the therapy of many microbial infections. As the bacterial resistance to antibiotic therapy is appearing as an increasingly significant threat to public health, the development of aminoglycoside antibiotics with extended antibacterial spectrum and potency, devoid of nephro- and ototoxicity, and evading the resistance process returns to the focus of researchers. In this review, various developments brought to the aminoglycoside family of antibiotics effective against resistant bacteria have been described, focused on chem. modifications, drug-modifying enzyme inhibitors, and conformationally constrained analogs, as well as related antibacterial compds., with the hope to provide information useful in rational design of novel antibiotics addressing bacterial resistance, and paving the way for new perspectives in antimicrobial therapy.
20
Armstrong, E. S., Kostrub, C. F., Cass, R. T., Moser, H. E., Serio, A. W., and Miller, G. H. (2012) in Antibiotic Discovery and Development (Dougherty, T. J., and Pucci, M. J., Eds.) pp 229– 269, Springer Science+Business Media, New York.
Google Scholar
There is no corresponding record for this reference.
21
Chandrika, N. T. and Garneau-Tsodikova, S. (2016) A Review of Patents (2011–2015) Towards Combating Resistance to and Toxicity of Aminoglycosides. MedChemComm 7, 50– 68, DOI: 10.1039/C5MD00453E
Google Scholar
21
A review of patents (2011-2015) towards combating resistance to and toxicity of aminoglycosides
Chandrika, Nishad Thamban; Garneau-Tsodikova, Sylvie
MedChemComm (2016), 7 (1), 50-68CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
Since the discovery of the first aminoglycoside (AG), streptomycin, in 1943, these broad-spectrum antibiotics have been extensively used for the treatment of Gram-neg. and Gram-pos. bacterial infections. The inherent toxicity (ototoxicity and nephrotoxicity) assocd. with their long-term use as well as the emergence of resistant bacterial strains have limited their usage. Structural modifications of AGs by AG-modifying enzymes, reduced target affinity caused by ribosomal modification, and decrease in their cellular concn. by efflux pumps have resulted in resistance towards AGs. However, the last decade has seen a renewed interest among the scientific community for AGs as exemplified by the recent influx of scientific articles and patents on their therapeutic use. In this review, we use a non-conventional approach to put forth this renaissance on AG development/application by summarizing all patents filed on AGs from 2011-2015 and highlighting some related publications on the most recent work done on AGs to overcome resistance and improving their therapeutic use while reducing ototoxicity and nephrotoxicity. We also present work towards developing amphiphilic AGs for use as fungicides as well as that towards repurposing existing AGs for potential newer applications.
22
Thamban Chandrika, N. and Garneau-Tsodikova, S. (2018) Comprehensive Review of Chemical Strategies for the Preparation of New Aminoglycosides and their Biological Activities. Chem. Soc. Rev. 47, 1189– 1249, DOI: 10.1039/C7CS00407A
Google Scholar
22
Comprehensive review of chemical strategies for the preparation of new aminoglycosides and their biological activities
Thamban Chandrika, Nishad; Garneau-Tsodikova, Sylvie
Chemical Society Reviews (2018), 47 (4), 1189-1249CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
A systematic anal. of all synthetic and chemoenzymic methodologies for the prepn. of aminoglycosides for a variety of applications (therapeutic and agricultural) reported in the scientific literature up to 2017 is presented. This comprehensive anal. of derivatization/generation of novel aminoglycosides and their conjugates is divided based on the types of modifications used to make the new derivs. Both the chem. strategies utilized and the biol. results obsd. are covered. Structure-activity relationships based on different synthetic modifications along with their implications for activity and ability to avoid resistance against different microorganisms are also presented.
23
Zárate, S. G., De la Cruz Claure, M. L., Benito-Arenas, R., Revuelta, R., Santana, A. G., and Bastida, A. (2018) Overcoming Aminoglycoside Enzymatic Resistance: Design of Novel Antibiotics and Inhibitors. Molecules 23, 284, DOI: 10.3390/molecules23020284
Google Scholar
23
Overcoming aminoglycoside enzymatic resistance: design of novel antibiotics and inhibitors
Zarate, Sandra G.; Claure, M. Luisa De la Cruz; Benito-Arenas, Raul; Revuelta, Julia; Santana, Andres G.; Bastida, Agatha
Molecules (2018), 23 (2), 284/1-284/18CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
Resistance to aminoglycoside antibiotics has had a profound impact on clin. practice. Despite their powerful bactericidal activity, aminoglycosides were one of the first groups of antibiotics to meet the challenge of resistance. The most prevalent source of clin. relevant resistance against these therapeutics is conferred by the enzymic modification of the antibiotic. Therefore, a deeper knowledge of the aminoglycoside-modifying enzymes and their interactions with the antibiotics and solvent is of paramount importance in order to facilitate the design of more effective and potent inhibitors and/or novel semisynthetic aminoglycosides that are not susceptible to modifying enzymes.
24
Takahashi, Y. and Igarashi, M. (2018) Destination of Aminoglycoside Antibiotics in the ‘Post-Antibiotic Era’. J. Antibiot. 71, 4– 14, DOI: 10.1038/ja.2017.117
Google Scholar
24
Destination of aminoglycoside antibiotics in the 'post-antibiotic era'
Takahashi, Yoshiaki; Igarashi, Masayuki
Journal of Antibiotics (2018), 71 (1), 4-14CODEN: JANTAJ; ISSN:0021-8820. (Nature Research)
A review. Aminoglycoside antibiotics (AGAs) were developed at the dawn of the antibiotics era and have significantly aided in the treatment of infectious diseases. Aminoglycosides have become one of the four major types of antibiotics in use today and, fortunately, still have an important role in the clin. treatment of severe bacterial infections. In this review, the current usage, modes of action and side effects of AGAs, along with the most common bacterial resistance mechanisms, are outlined. Finally, the recent development situation and possibility of new AGAs in the 'post-antibiotic era' are considered.
25
Aggen, J. B., Armstrong, E. S., Goldblum, A. A., Dozzo, P., Linsell, M. S., Gliedt, M. J., Hildebrandt, D. J., Feeney, L. A., Kubo, A., Matias, R. D., Lopez, S., Gomez, M., Wlasichuk, K. B., Diokno, R., Miller, G. H., and Moser, H. E. (2010) Synthesis and Spectrum of the Neoglycoside ACHN-490. Antimicrob. Agents Chemother. 54, 4636– 4642, DOI: 10.1128/AAC.00572-10
Google Scholar
25
Synthesis and spectrum of the neoglycoside ACHN-490
Aggen, James B.; Armstrong, Eliana S.; Goldblum, Adam A.; Dozzo, Paola; Linsell, Martin S.; Gliedt, Micah J.; Hildebrandt, Darin J.; Feeney, Lee Ann; Kubo, Aya; Matias, Rowena D.; Lopez, Sara; Gomez, Marcela; Wlasichuk, Kenneth B.; Diokno, Raymond; Miller, George H.; Moser, Heinz E.
Antimicrobial Agents and Chemotherapy (2010), 54 (11), 4636-4642CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
ACHN-490 is a neoglycoside, or "next-generation" aminoglycoside (AG), that has been identified as a potentially useful agent to combat drug-resistant bacteria emerging in hospitals and health care facilities around the world. A focused medicinal chem. campaign produced a collection of over 400 sisomicin analogs from which ACHN-490 was selected. The authors tested ACHN-490 against two panels of Gram-neg. and Gram-pos. pathogens, many of which harbored AG resistance mechanisms. Unlike legacy AGs, ACHN-490 was active against strains expressing known AG-modifying enzymes, including the three most common such enzymes found in Enterobacteriaceae. ACHN-490 inhibited the growth of AG-resistant Enterobacteriaceae (MIC90, ≤4 μg/mL), with the exception of Proteus mirabilis and indole-pos. Proteae (MIC90, 8 μg/mL and 16 μg/mL, resp.). ACHN-490 was more active alone in vitro against Pseudomonas aeruginosa and Acinetobacter baumannii isolates with AG-modifying enzymes than against those with altered permeability/efflux. The MIC90 of ACHN-490 against AG-resistant staphylococci was 2 μg/mL. Due to its promising in vitro and in vivo profiles, ACHN-490 has been advanced into clin. development as a new antibacterial agent.
26
Cox, G., Ejim, L., Stogios, P. J., Koteva, K., Bordeleau, E., Evdokimova, E., Sieron, A. O., Savchenko, A., Serio, A. W., Krause, K. M., and Wright, G. D. (2018) Plazomicin Retains Antibiotic Activity against Most Aminoglycoside Modifying Enzymes. ACS Infect. Dis. 4, 980– 987, DOI: 10.1021/acsinfecdis.8b00001
Google Scholar
26
Plazomicin Retains Antibiotic Activity against Most Aminoglycoside Modifying Enzymes
Cox, Georgina; Ejim, Linda; Stogios, Peter J.; Koteva, Kalinka; Bordeleau, Emily; Evdokimova, Elena; Sieron, Arthur O.; Savchenko, Alexei; Serio, Alisa W.; Krause, Kevin M.; Wright, Gerard D.
ACS Infectious Diseases (2018), 4 (6), 980-987CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)
Plazomicin is a next-generation, semisynthetic aminoglycoside antibiotic currently under development for the treatment of infections due to multidrug-resistant Enterobacteriaceae. The compd. was designed by chem. modification of the natural product sisomicin to provide protection from common aminoglycoside modifying enzymes that chem. alter these drugs via N-acetylation, O-adenylylation, or O-phosphorylation. In this study, plazomicin was profiled against a panel of isogenic strains of Escherichia coli individually expressing twenty-one aminoglycoside resistance enzymes. Plazomicin retained antibacterial activity against 15 of the 17 modifying enzyme-expressing strains tested. Expression of only two of the modifying enzymes, aac(2')-Ia and aph(2'')-IVa, decreased plazomicin potency. On the other hand, expression of 16S rRNA ribosomal methyltransferases results in a complete lack of plazomicin potency. In vitro enzymic assessment confirmed that AAC(2')-Ia and APH(2'')-IVa (aminoglycoside acetyltransferase, AAC; aminoglycoside phosphotransferase, APH) were able to utilize plazomicin as a substrate. AAC(2')-Ia and APH(2'')-IVa are limited in their distribution to Providencia stuartii and Enterococci, resp. These data demonstrate that plazomicin is not modified by a broad spectrum of common aminoglycoside modifying enzymes including those commonly found in Enterobacteriaceae. However, plazomicin is inactive in the presence of 16S rRNA ribosomal methyltransferases, which should be monitored in future surveillance programs.
27
Magnet, S. and Blanchard, J. S. (2005) Molecular Insights into Aminoglycoside Action and Resistance. Chem. Rev. 105, 477– 497, DOI: 10.1021/cr0301088
Google Scholar
27
Molecular Insights into Aminoglycoside Action and Resistance
Magnet, Sophie; Blanchard, John S.
Chemical Reviews (Washington, DC, United States) (2005), 105 (2), 477-497CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
A review. The review discusses the mechanism of action, properties, clin. uses of, and resistance to aminoglycoside antibiotics.
28
Ramirez, M. S. and Tolmasky, M. E. (2010) Aminoglycoside Modifiying Enzymes. Drug Resist. Updates 13, 151– 171, DOI: 10.1016/j.drup.2010.08.003
Google Scholar
28
Aminoglycoside modifying enzymes
Ramirez, Maria S.; Tolmasky, Marcelo E.
Drug Resistance Updates (2010), 13 (6), 151-171CODEN: DRUPFW; ISSN:1368-7646. (Elsevier Ltd.)
A review. Aminoglycosides have been an essential component of the armamentarium in the treatment of life-threatening infections. Unfortunately, their efficacy has been reduced by the surge and dissemination of resistance. In some cases the levels of resistance reached the point that rendered them virtually useless. Among many known mechanisms of resistance to aminoglycosides, enzymic modification is the most prevalent in the clin. setting. Aminoglycoside modifying enzymes catalyze the modification at different -OH or -NH2 groups of the 2-deoxystreptamine nucleus or the sugar moieties and can be nucleotidyltranferases, phosphotransferases, or acetyltransferases. The no. of aminoglycoside modifying enzymes identified to date as well as the genetic environments where the coding genes are located is impressive and there is virtually no bacteria that is unable to support enzymic resistance to aminoglycosides. Aside from the development of new aminoglycosides refractory to as many as possible modifying enzymes there are currently two main strategies being pursued to overcome the action of aminoglycoside modifying enzymes. Their successful development would extend the useful life of existing antibiotics that have proven effective in the treatment of infections. These strategies consist of the development of inhibitors of the enzymic action or of the expression of the modifying enzymes.
29
Garneau-Tsodikova, S. and Labby, K. J. (2016) Mechanisms of Resistance to Aminoglycoside Antibiotics: Overview and Perspectives. MedChemComm 7, 11– 27, DOI: 10.1039/C5MD00344J
Google Scholar
29
Mechanisms of resistance to aminoglycoside antibiotics: overview and perspectives
Garneau-Tsodikova, Sylvie; Labby, Kristin J.
MedChemComm (2016), 7 (1), 11-27CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
A review. Aminoglycoside (AG) antibiotics are used to treat many Gram-neg. and some Gram-pos. infections and, importantly, multidrug-resistant tuberculosis. Among various bacterial species, resistance to AGs arises through a variety of intrinsic and acquired mechanisms. The bacterial cell wall serves as a natural barrier for small mols. such as AGs and may be further fortified via acquired mutations. Efflux pumps work to expel AGs from bacterial cells, and modifications here too may cause further resistance to AGs. Mutations in the ribosomal target of AGs, while rare, also contribute to resistance. Of growing clin. prominence is resistance caused by ribosome methyltransferases. By far the most widespread mechanism of resistance to AGs is the inactivation of these antibiotics by AG-modifying enzymes. We provide here an overview of these mechanisms by which bacteria become resistant to AGs and discuss their prevalence and potential for clin. relevance.
30
Bacot-Davis, V. R., Bassenden, A. V., and Berghuis, A. M. (2016) Drug-target Networks in Aminoglycoside Resistance: Hierarchy of Priority in Structural Drug Design. MedChemComm 7, 103– 113, DOI: 10.1039/C5MD00384A
Google Scholar
30
Drug-target networks in aminoglycoside resistance: hierarchy of priority in structural drug design
Bacot-Davis, Valjean R.; Bassenden, Angelia V.; Berghuis, Albert M.
MedChemComm (2016), 7 (1), 103-113CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
Antibiotic resistance is a multifactorial problem that demands multifaceted strategies to address. Here we present a drug-target network anal. of the clin. most prominent mechanism of resistance to aminoglycoside antibiotics, i.e. enzyme mediated modification of the antibiotics. This drug-target network displays prominent resistance preferences for 4,6-disubstituted aminoglycosides such as tobramycin and gentamicin, reflective of their extensive clin. usage. Further anal. also highlights aminoglycosides that remain more resilient to modifications by various bacterial resistance enzymes. This aminoglycoside resistance drug-target network conveys a compelling case for prioritization of next-generation aminoglycosides development exploiting 4,5-disubstituted and non-deoxystreptamine aminoglycoside scaffolds to surmount rising drug-resistance, in conjunction with advancing inhibitor/adjuvant leads effective against multiple aminoglycoside modifying enzyme.
31
Doi, Y., Wachino, J. I., and Arakawa, Y. (2016) Aminoglycoside Resistance: The Emergence of Acquired 16S Ribosomal RNA Methyltransferases. Infect. Dis. Clin. North Am. 30, 523– 537, DOI: 10.1016/j.idc.2016.02.011
Google Scholar
31
Aminoglycoside Resistance: The Emergence of Acquired 16S Ribosomal RNA Methyltransferases
Doi Yohei; Wachino Jun-Ichi; Arakawa Yoshichika
Infectious disease clinics of North America (2016), 30 (2), 523-537 ISSN:.
Aminoglycoside-producing Actinobacteria are known to protect themselves from their own aminoglycoside metabolites by producing 16S ribosomal RNA methyltransferase (16S-RMTase), which prevents them from binding to the 16S rRNA targets. Ten acquired 16S-RMTases have been reported from gram-negative pathogens. Most of them posttranscriptionally methylate residue G1405 of 16S rRNA resulting in high-level resistance to gentamicin, tobramycin, amikacin, and plazomicin. Strains that produce 16S-RMTase are frequently multidrug-resistant or even extensively drug-resistant. Although the direct clinical impact of high-level aminoglycoside resistance resulting from production of 16S-RMTase is yet to be determined, ongoing spread of this mechanism will further limit treatment options for multidrug-resistant and extensively drug-resistant gram-negative infections.
32
Sonousi, A., Sarpe, V. A., Brilkova, M., Schacht, J., Vasella, A., Böttger, E. C., and Crich, D. (2018) Effects of the 1-N-(4-Amino-2S-hydroxybutyryl) and 6′-N-(2-Hydroxyethyl) Substituents on Ribosomal Selectivity, Cochleotoxicity and Antibacterial Activity in the Sisomicin Class of Aminoglycoside Antibiotics. ACS Infect. Dis. 4, 1114– 1120, DOI: 10.1021/acsinfecdis.8b00052
Google Scholar
32
Effects of the 1-N-(4-Amino-2S-hydroxybutyryl) and 6'-N-(2-Hydroxyethyl) Substituents on Ribosomal Selectivity, Cochleotoxicity, and Antibacterial Activity in the Sisomicin Class of Aminoglycoside Antibiotics
Sonousi, Amr; Sarpe, Vikram A.; Brilkova, Margarita; Schacht, Jochen; Vasella, Andrea; Bottger, Erik C.; Crich, David
ACS Infectious Diseases (2018), 4 (7), 1114-1120CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)
Syntheses of the 6'-N-(2-hydroxyethyl) and 1-N-(4-amino-2S-hydroxybutyryl) derivs. of the 4,6-aminoglycoside sisomicin and that of the doubly modified 1-N-(4-amino-2S-hydroxybutyryl)-6'-N-(2-hydroxyethyl) deriv. known as plazomicin are reported together with their antibacterial and antiribosomal activities and selectivities. The 6'-N-(2-hydroxyethyl) modification results in a moderate increase in prokaryotic/eukaryotic ribosomal selectivity, whereas the 1-N-(4-amino-2S-hydroxybutyryl) modification has the opposite effect. When combined in plazomicin the effects of the two groups on ribosomal selectivity are cancelled leading to the prediction that plazomicin will exhibit comparable ototoxicity to the parent and to the current clin. AGAs gentamicin and tobramycin, as borne out by ex-vivo studies with mouse cochlear ex-plants. The 6'-N-(2-hydroxyethyl) modification restores antibacterial activity in the presence of the AAC(6') aminoglycoside-modifying enzymes, while the 1-N-(4-amino-2S-hydroxybutyryl) modification overcomes resistance to the AAC(2') class, but is still affected by the AAC(3) class. Neither modification is able to circumvent the ArmA ribosomal methyltransferase-induced aminoglycoside resistance. The use of phenyltriazenyl protection for the secondary amino group of sisomicin facilitates synthesis of each deriv. and their characterization through the provision of sharp NMR spectra for all intermediates.
33
Livermore, D. M., Mushtaq, S., Warner, M., Zhang, J.-C., Maharjan, S., Doumith, M., and Woodford, N. (2011) Activity of Aminoglycosides, Including ACHN-490, Against Carbapenem-resistant Enterobacteriaceae Isolates. J. Antimicrob. Chemother. 66, 48– 53, DOI: 10.1093/jac/dkq408
Google Scholar
33
Activity of aminoglycosides, including ACHN-490, against carbapenem-resistant Enterobacteriaceae isolates
Livermore, D. M.; Mushtaq, S.; Warner, M.; Zhang, J.-C.; Maharjan, S.; Doumith, M.; Woodford, N.
Journal of Antimicrobial Chemotherapy (2011), 66 (1), 48-53CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
The emergence of carbapenemases in Enterobacteriaceae is driving a search for therapeutic alternatives. The authors tested ACHN-490, a sisomicin deriv. that evades all plasmid-mediated aminoglycoside-modifying enzymes, against 82 carbapenem-resistant Enterobacteriaceae isolates. Comparators included internationally and locally available aminoglycosides. The isolates variously had KPC (n = 12), SME-1 (n = 1), IMP (n = 13), VIM (n = 5), NDM (n = 17) or OXA-48 (n = 19) carbapenemases, or had combinations of impermeability with AmpC (n = 5) or extended-spectrum β-lactamases (n = 10). They included 53 Klebsiella spp., 19 Enterobacter spp., 6 Escherichia coli and 4 others; most were multiresistant. Genes were identified by PCR and sequencing; MICs were measured by CLSI agar diln. ACHN-490 was active at ≤2 mg/L against all 65 isolates with carbapenem resistance mechanisms other than NDM enzyme, mostly with MICs of 0.12-0.5 mg/L; isepamicin was active against 63/65 at ≤8 mg/L. In contrast, 35% were resistant to gentamicin at 4 mg/L, 61% to tobramycin at 4 mg/L and 20% to amikacin at 16 mg/L. However, 16 of the 17 isolates with NDM-1 enzyme were resistant to ACHN-490, with MICs ≥64 mg/L, and these were cross-resistant to all other human-use aminoglycosides tested. Their behavior was assocd. with ArmA and RmtC 16S rRNA methylases. Apramycin (a veterinary aminoglycoside) retained its full activity, with MICs of 4-8 mg/L vs. strains with armA or rmtC, though resistance was seen in one Klebsiella pneumoniae with AAC(3)-IV (MIC ≥256 mg/L). ACHN-490 has potent activity vs. carbapenem-resistant isolates, except those also harboring 16S rRNA methylases; isepamicin is also widely active, though less potent than ACHN-490. Evasion of 16S rRNA methylases by apramycin is noteworthy and may provide a starting point for future aminoglycoside development.
34
Taylor, E., Sriskandan, S., Woodford, N., and Hopkins, K. L. (2018) High Prevalence of 16S rRNA Methyltransferases Among Carbapenenase-producing Enterobacteriaceae in the UK and Ireland. Int. J. Antimicrob. Agents 52, 278– 282, DOI: 10.1016/j.ijantimicag.2018.03.016
Google Scholar
34
High prevalence of 16S rRNA methyltransferases among carbapenemase-producing Enterobacteriaceae in the UK and Ireland
Taylor, Emma; Sriskandan, Shiranee; Woodford, Neil; Hopkins, Katie L.
International Journal of Antimicrobial Agents (2018), 52 (2), 278-282CODEN: IAAGEA; ISSN:0924-8579. (Elsevier B.V.)
The emergence of 16S rRNA methyltransferases (16S RMTases) worldwide is a growing concern due to their ability to confer high-level resistance (min. inhibitory concns. (MICs) >256 mg/L) to all clin. relevant aminoglycosides. As the occurrence of 16S RMTases in the United Kingdom has not been investigated to date, we screened 806 Enterobacteriaceae isolates displaying high-level aminoglycoside resistance (amikacin, gentamicin and tobramycin MICs ≥64, ≥32 and ≥32 mg/L, resp.) for 16S RMTases either by analyzing whole-genome sequence (WGS) data (which were available for 449 isolates) or by polymerase chain reaction. A total of 94.5% (762/806) pan-aminoglycoside-resistant Enterobacteriaceae were pos. for one or more 16S RMTase genes; armA was the most common (340, 44.6%) followed by rmtC (146, 19.2%), rmtF (137, 18.0%), rmtB (87, 11.4%) and various two-gene combinations (52, 6.8%). Most (93.4%; 712/762) 16S RMTase producers also carried acquired carbapenemase genes, with blaNDM the most common (592/712; 83.1%). Addnl., high-risk bacterial clones assocd. with blaNDM were identified in the subset of isolates with WGS data. These included Escherichia coli sequence types (STs) 405 (21.8%, 19/87), 167 (20.7%, 18/87) 410 (12.6%, 11/87) and K. pneumoniae STs 14 (35.6%, 112/315), 231 (15.6%, 49/315) and 147 (10.5%, 33/315). These accounted for 4.2% (15/358), 5.0% (18/358), 3.1% (11/358), 28.2% (101/358), 3.1% (11/358) and 7.0% (25/358) blaNDM-producing isolates, resp. This study shows that 16S RMTases occur in the UK and Ireland and carbapenemases are particularly prevalent in 16S RMTase-producing Enterobacteriaceae. This assocn. poses a risk to the treatment of multidrug-resistant Gram-neg. infections in the clin. setting.
35
Piekarska, K., Zacharczuk, K., Wołkowicz, T., Rzeczkowska, M., Bareja, E., Olak, M., and Gierczyński, R. (2016) Distribution of 16S rRNA Methylases Among Different Species of Aminoglycoside-Resistant Enterobacteriaceae in a Tertiary Care Hospital in Poland. Adv. Clin. Exp. Med. 25, 539– 544, DOI: 10.17219/acem/34150
Google Scholar
35
Distribution of 16S rRNA Methylases Among Different Species of Aminoglycoside-Resistant Enterobacteriaceae in a Tertiary Care Hospital in Poland
Piekarska Katarzyna; Zacharczuk Katarzyna; Wolkowicz Tomasz; Rzeczkowska Magdalena; Gierczynski Rafal; Bareja Elzbieta; Olak Monika
Advances in clinical and experimental medicine : official organ Wroclaw Medical University (2016), 25 (3), 539-44 ISSN:1899-5276.
BACKGROUND: Aminoglycosides are a group of antimicrobial agents still the most commonly used in the treatment of life-threatening bacterial infections in human and animals. The emergence and spread of 16S rRNA methylases, which confer high-level resistance to the majority of clinically relevant aminoglycosides, constitute a major public health concern. OBJECTIVES: Our goal was to evaluate the distribution of 16S rRNA methylases among different species of Enterobacteriaceae during a five month-long survey in a tertiary hospital in Warszawa, Poland. MATERIAL AND METHODS: In the survey, a total of 1770 non-duplicate clinical isolates were collected from all hospital wards in a tertiary hospital in Warszawa, Poland. The survey was conducted between 19 April and 19 September 2010. The ability to produce 16S rRNA methylase was examined by determining MICs for gentamicin, kanamycin, amikacin by means of the agar dilution method. The isolates resistant to high concentration of aminoglycosides were PCR tested for genes: armA, rmtA, rmtB and rmtC. PCR products were subjected to DNA sequencing by the Sanger method. The genetic similarity of the ArmA-producing isolates was analysed by pulsed-filed gel electrophoresis (PFGE). RESULTS: ArmA was the only 16S rRNA methylase detected in 20 of 1770 tested isolates. The overall prevalence rate of ArmA was 1.13%. In K. pneumoniae (n = 742), P. mirabilis (n = 130), and E. cloacae (n = 253) collected in the survey, the prevalence of ArmA was 0.4%, 0.8% and 5.9%, respectively. The PFGE revealed both horizontal and clonal spread of the armA gene in the hospital. CONCLUSIONS: The prevalence of 16S rRNA methylase ArmA reported in this study is significantly higher than observed in other countries in Europe.
36
Vicens, Q. and Westhof, E. (2003) Molecular Recognition of Aminoglycoside Antibiotics by Ribosomal RNA and Resistance Enzymes: An Analysis of X-Ray Crystal Structures. Biopolymers 70, 42– 57, DOI: 10.1002/bip.10414
Google Scholar
36
Molecular recognition of aminoglycoside antibiotics by ribosomal RNA and resistance enzymes: An analysis of X-ray crystal structures
Vicens, Quentin; Westhof, Eric
Biopolymers (2003), 70 (1), 42-57CODEN: BIPMAA; ISSN:0006-3525. (John Wiley & Sons, Inc.)
A review. The potential of RNA mols. to be used as therapeutic targets by small inhibitors is now well established. In this fascinating wide-open field, aminoglycoside antibiotics constitute the most studied family of RNA binding drugs. Within the last three years, several x-ray crystal structures were solved for aminoglycosides complexed to one of their main natural targets in the bacterial cell, the decoding aminoacyl-tRNA site (A site). Other crystallog. structures have revealed the binding modes of aminoglycosides to the three existing types of resistance-assocd. enzymes. The present review summarizes the various aspects of the mol. recognition of aminoglycosides by these natural RNA or protein receptors. The anal. and the comparisons of the detailed interactions offer insights that are helpful in designing new generations of antibiotics.
37
O’Connor, S., Lam, L. K. T., Jones, N. D., and Chaney, M. O. (1976) Apramycin, a Unique Aminocyclitol Antibiotic. J. Org. Chem. 41, 2087– 2092, DOI: 10.1021/jo00874a003
Google Scholar
37
Apramycin, a unique aminocyclitol antibiotic
O'Connor, Sean; Lam, L. K. T.; Jones, Noel D.; Chaney, Michael O.
Journal of Organic Chemistry (1976), 41 (12), 2087-92CODEN: JOCEAH; ISSN:0022-3263.
Apramycin produced by a strain of Streptomyces tenebrarius, does not fall into the tobramycin, kanamycin, gentamicin group and a detailed examination of its structure involving degradative, synthetic, and spectroscopic anal. leads to the assignment of the unusual structure I. The main features of which are a 4-amino-4-deoxy-D-glucose moiety, a 1-1' sugar linkage, and an octadiose which exists as a rigid bicyclic system. The proposed structure is confirmed by an x-ray diffraction study.
38
Smith, K. P. and Kirby, J. E. (2016) Evaluation of Apramycin Activity Against Carbapenem-Resistant and -Susceptible Strains of Enterobacteriaceae. Diagn. Microbiol. Infect. Dis. 86, 439– 441, DOI: 10.1016/j.diagmicrobio.2016.09.002
Google Scholar
38
Evaluation of apramycin activity against carbapenem-resistant and -susceptible strains of Enterobacteriaceae
Smith, Kenneth P.; Kirby, James E.
Diagnostic Microbiology and Infectious Disease (2016), 86 (4), 439-441CODEN: DMIDDZ; ISSN:0732-8893. (Elsevier)
We evaluated activity of apramycin, a non-ototoxic/non-nephrotoxic aminocyclitol against 141 clin. Enterobacteriaceae isolates, 51% of which were non-susceptible to carbapenems (CRE). Among CRE, 70.8% were apramycin susceptible, which compared favorably to aminoglycosides in current clin. use. Our data suggest that apramycin deserves further investigation as a repurposed, anti-CRE therapeutic.
39
Hu, Y., Liu, L., Zhang, X., Feng, Y., and Zong, Z. (2017) In Vitro Activity of Neomycin, Streptomycin, Paromomycin and Apramycin Against Carbapenem-resistant Enterobacteriaceae Clinical Strains. Front. Microbiol. 8, 2275, DOI: 10.3389/fmicb.2017.02275
Google Scholar
39
In Vitro Activity of Neomycin, Streptomycin, Paromomycin and Apramycin against Carbapenem-Resistant Enterobacteriaceae Clinical Strains
Hu Ya; Liu Lu; Zhang Xiaoxia; Feng Yu; Zong Zhiyong; Hu Ya; Liu Lu; Zhang Xiaoxia; Feng Yu; Zong Zhiyong; Zong Zhiyong; Zong Zhiyong
Frontiers in microbiology (2017), 8 (), 2275 ISSN:1664-302X.
We determined the in vitro susceptibility of four aminoglycosides, which are not of the 4,6-disubstituted deoxystreptamine (DOS) subclass against a collection of carbapenem-resistant Enterobacteriaceae (CRE). CRE clinical strains (n = 134) were collected from multiple hospitals in China and carried blaNDM (blaNDM-1, blaNDM-5 or blaNDM-7; n = 66), blaKPC-2 (n = 62) or blaIMP-4 (n = 7; including one carrying blaNDM-1 and blaIMP-4). MICs of neomycin, paromomycin, streptomycin and apramycin as well as three 4,6-disubstituted DOS aminoglycosides (amikacin, gentamicin and tobramycin) were determined using the broth microdilution with breakpoints defined by the Clinical Laboratory Standards Institute (for amikacin, gentamicin and tobramycin), US Food and Drug Administration (streptomycin), the National Antimicrobial Resistance Monitoring System (apramycin) or la Societe Francaise de Microbiologie (neomycin and paromomycin). Apramycin-resistant strains were subjected to whole genome sequencing using Illumina X10 platform. Among CRE strains, 65.7, 64.9, 79.1, and 95.5% were susceptible to neomycin (MIC50/MIC90, 8/256 μg/ml), paromomycin (4/>256 μg/ml), streptomycin (16/256 μg/ml) and apramycin (4/8 μg/ml), respectively, while only 55.2, 28.4, and 35.1% were susceptible to amikacin (32/>256 μg/ml), gentamicin (128/>256 μg/ml) and tobramycin (64/>256 μg/ml), respectively. Six CRE strains including five Escherichia coli of different sequence types and one Klebsiella pneumoniae were resistant to apramycin and the apramycin-resistant gene aac(3)-IVa was detected in all of these strains. In conclusion, neomycin, paromomycin, streptomycin and apramycin retain activity against most CRE strains. Although none of these non-4,6-disubstituted DOS aminoglycosides are suitable for intravenous use in human at present, these agents warrant further investigations to be used against CRE infections.
40
Kang, A. D., Smith, K. P., Eliopoulos, G. M., Berg, A. H., McCoy, C., and Kirby, J. E. (2017) In vitro Apramycin Activity Against Multidrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa. Diagn. Microbiol. Infect. Dis. 88, 188– 191, DOI: 10.1016/j.diagmicrobio.2017.03.006
Google Scholar
40
Invitro Apramycin Activity against multidrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa
Kang, Anthony D.; Smith, Kenneth P.; Eliopoulos, George M.; Berg, Anders H.; McCoy, Christopher; Kirby, James E.
Diagnostic Microbiology and Infectious Disease (2017), 88 (2), 188-191CODEN: DMIDDZ; ISSN:0732-8893. (Elsevier)
The in vitro activity of apramycin was compared to that of amikacin, gentamicin, and tobramycin against multidrug-resistant, extensively drug-resistant, and pandrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa. Apramycin demonstrated an MIC50/MIC90 of 8/32 μg/mL for A. baumannii and 16/32 μg/mL for P. aeruginosa. Only 2% of A. baumannii and P. aeruginosa had an MIC greater than an epidemiol. cutoff value of 64 μg/mL. In contrast, the MIC50/MIC90 for amikacin, gentamicin, and tobramycin were ≥64/>256 μg/mL for A. baumannii with 57%, 95%, and 74% of isolates demonstrating resistance, resp., and the MIC50/MIC90 were ≥8/256 μg/mL for P. aeruginosa with 27%, 50%, and 57% of strains demonstrating resistance, resp. Apramycin appears to offer promising in vitro activity against highly resistant pathogens. It therefore may warrant further pre-clin. study to assess potential for repurposing as a human therapeutic and relevance as a scaffold for further medicinal chem. exploration.
41
Juhas, M., Widlake, E., Teo, J., Huseby, D. L., Tyrrell, J. M., Polikanov, Y., Ercan, O., Petersson, A., Cao, S., Aboklaish, A. F., Rominski, A., Crich, D., Böttger, E. C., Walsh, T. R., Hughes, D. E., and Hobbie, S. N. (2019) In-vitro Activity of Apramycin Against Multidrug-, Carbapenem-, and Aminoglycoside-Resistant Enterobacteriaceae and Acinetobacter baumannii. J. Antimicrob. Chemother. 74, 944– 952, DOI: 10.1093/jac/dky546
Google Scholar
41
In vitro activity of apramycin against multidrug-, carbapenem- and aminoglycoside-resistant Enterobacteriaceae and Acinetobacter baumannii
Juhas, Mario; Widlake, Emma; Teo, Jeanette; Huseby, Douglas L.; Tyrrell, Jonathan M.; Polikanov, Yury S.; Ercan, Onur; Petersson, Anna; Cao, Sha; Aboklaish, Ali F.; Rominski, Anna; Crich, David; Bottger, Erik C.; Walsh, Timothy R.; Hughes, Diarmaid; Hobbie, Sven N.
Journal of Antimicrobial Chemotherapy (2019), 74 (4), 944-952CODEN: JACHDX; ISSN:1460-2091. (Oxford University Press)
Objectives: Widespread antimicrobial resistance often limits the availability of therapeutic options to only a few last-resort drugs that are themselves challenged by emerging resistance and adverse side effects. Apramycin, an aminoglycoside antibiotic, has a unique chem. structure that evades almost all resistance mechanisms including the RNA methyltransferases frequently encountered in carbapenemase-producing clin. isolates. This study evaluates the in vitro activity of apramycin against multidrug-, carbapenem- and aminoglycoside-resistant Enterobacteriaceae and Acinetobacter baumannii, and provides a rationale for its superior antibacterial activity in the presence of aminoglycoside resistance determinants. Methods: A thorough antibacterial assessment of apramycin with 1232 clin. isolates from Europe, Asia, Africa and South America was performed by std. CLSI broth microdilution testing. WGS and susceptibility testing with an engineered panel of aminoglycoside resistance-conferring determinants were used to provide a mechanistic rationale for the breadth of apramycin activity. Results: MIC distributions and MIC90 values demonstrated broad antibacterial activity of apramycin against Escherichia coli, Klebsiella pneumoniae, Enterobacter spp., Morganella morganii, Citrobacter freundii, Providencia spp., Proteus mirabilis, Serratia marcescens and A. baumannii. Genotypic anal. revealed the variety of aminoglycoside-modifying enzymes and rRNA methyltransferases that rendered a remarkable proportion of clin. isolates resistant to std.-of-care aminoglycosides, but not to apramycin. Screening a panel of engineered strains each with a single well-defined resistance mechanism further demonstrated a lack of cross-resistance to gentamicin, amikacin, tobramycin and plazomicin. Conclusions: Its superior breadth of activity renders apramycin a promising drug candidate for the treatment of systemic Gram-neg. infections that are resistant to treatment with other aminoglycoside antibiotics.
42
(2018) Tackling Antimicrobial Resistance: ENABLE Selects First Clinical Candidate, Innovative Medicines Initiative. https://www.imi.europa.eu/projects-results/project-factsheets/enable (accessed Feb 12, 2019).
Google Scholar
There is no corresponding record for this reference.
43
Perez-Fernandez, D., Shcherbakov, D., Matt, T., Leong, N. C., Kudyba, I., Duscha, S., Boukari, H., Patak, R., Dubbaka, S. R., Lang, K., Meyer, M., Akbergenov, R., Freihofer, P., Vaddi, S., Thommes, P., Ramakrishnan, V., Vasella, A., and Böttger, E. C. (2014) 4′-O-Substitutions Determine Aminoglycoside Selectivity at the Drug Target Level. Nat. Commun. 5, 3112, DOI: 10.1038/ncomms4112
Google Scholar
43
4'-O-substitutions determine selectivity of aminoglycoside antibiotics
Perez-Fernandez Deborah; Shcherbakov Dmitri; Matt Tanja; Duscha Stefan; Boukari Heithem; Meyer Martin; Akbergenov Rashid; Freihofer Pietro; Bottger Erik C; Leong Ng Chyan; Kudyba Iwona; Patak Rashmi; Dubbaka Srinivas Reddy; Vasella Andrea; Lang Kathrin; Ramakrishnan V; Vaddi Swapna; Thommes Pia
Nature communications (2014), 5 (), 3112 ISSN:.
Clinical use of 2-deoxystreptamine aminoglycoside antibiotics, which target the bacterial ribosome, is compromised by adverse effects related to limited drug selectivity. Here we present a series of 4',6'-O-acetal and 4'-O-ether modifications on glucopyranosyl ring I of aminoglycosides. Chemical modifications were guided by measuring interactions between the compounds synthesized and ribosomes harbouring single point mutations in the drug-binding site, resulting in aminoglycosides that interact poorly with the drug-binding pocket of eukaryotic mitochondrial or cytosolic ribosomes. Yet, these compounds largely retain their inhibitory activity for bacterial ribosomes and show antibacterial activity. Our data indicate that 4'-O-substituted aminoglycosides possess increased selectivity towards bacterial ribosomes and little activity for any of the human drug-binding pockets.
44
Duscha, S., Boukari, H., Shcherbakov, D., Salian, S., Silva, S., Kendall, A., Kato, T., Akbergenov, R., Perez-Fernandez, D., Bernet, B., Vaddi, S., Thommes, P., Schacht, J., Crich, D., Vasella, A., and Böttger, E. C. (2014) Identification and Evaluation of Improved 4′-O-(Alkyl) 4,5-Disubstituted 2-Deoxystreptamines as Next Generation Aminoglycoside Antibiotics. mBio 5, e01827– 14, DOI: 10.1128/mBio.01827-14
Google Scholar
44
Identification and evaluation of improved 4'-O-(Alkyl) 4,5-disubstituted 2-deoxystreptamines as next-generation aminoglycoside antibiotics
Duscha, Stefan; Boukari, Heithem; Shcherbakov, Dimitri; Salian, Sumantha; Silva, Sandrina; Kendall, Ann; Kato, Takayuki; Akbergenov, Rashid; Perez-Fernandez, Deborah; Bernet, Bruno; Vaddi, Swapna; Thommes, Pia; Schacht, Jochen; Crich, David; Vasella, Andrea; Boettger, Erik C.
mBio (2014), 5 (5), e01827-14/1-e01827-14/11CODEN: MBIOCL; ISSN:2150-7511. (American Society for Microbiology)
The emerging epidemic of drug resistance places the development of efficacious and safe antibiotics in the spotlight of current research. Here, we report the design of next-generation aminoglycosides. Discovery efforts were driven by rational synthesis focusing on 4' alkylations of the aminoglycoside paromomycin, with the goal to alleviate the most severe and disabling side effect of aminoglycosides-irreversible hearing loss. Compds. were evaluated for target activity in in vitro ribosomal translation assays, antibacterial potency against selected pathogens, cytotoxicity against mammalian cells, and in vivo ototoxicity. The results of this study produced potent compds. with excellent selectivity at the ribosomal target, promising antibacterial activity, and little, if any, ototoxicity upon chronic administration. The favorable biocompatibility profile combined with the promising antibacterial activity emphasizes the potential of next-generation aminoglycosides in the treatment of infectious diseases without the risk of ototoxicity.
45
Matsushita, T., Chen, W., Juskeviciene, R., Teo, Y., Shcherbakov, D., Vasella, A., Böttger, E. C., and Crich, D. (2015) Influence of 4′-O-Glycoside Constitution and Configuration on Ribosomal Selectivity of Paromomycin. J. Am. Chem. Soc. 137, 7706– 7717, DOI: 10.1021/jacs.5b02248
Google Scholar
45
Influence of 4'-O-Glycoside Constitution and Configuration on Ribosomal Selectivity of Paromomycin
Matsushita, Takahiko; Chen, Weiwei; Juskeviciene, Reda; Teo, Youjin; Shcherbakov, Dimitri; Vasella, Andrea; Bottger, Erik C.; Crich, David
Journal of the American Chemical Society (2015), 137 (24), 7706-7717CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
A series of 20 4'-O-glycosides of the aminoglycoside antibiotic paromomycin were synthesized and evaluated for their ability to inhibit protein synthesis by bacterial, mitochondrial and cytosolic ribosomes. Target selectivity, i.e., inhibition of the bacterial ribosome over eukaryotic mitochondrial and cytosolic ribosomes, which is predictive of antibacterial activity with reduced ototoxicity and systemic toxicity, was greater for the equatorial than for the axial pyranosides, and greater for the D-pentopyranosides than for the L-pentopyranosides and D-hexopyranosides. In particular, 4'-O-β-D-xylopyranosyl paromomycin shows antibacterial ribosomal activity comparable to that of paromomycin, but is significantly more selective showing considerably reduced affinity for the cytosolic ribosome and for the A1555G mutant mitochondrial ribosome assocd. with hyper-susceptibility to drug-induced ototoxicity. Compd. antibacterial ribosomal activity correlates with antibacterial activity, and the ribosomally more active compds. show activity against Escherichia coli, Klebsiella pneumonia, Enterobacter cloacae, Acinetobacter baumannii, and methicillin-resistant Staphylococcus aureus (MRSA). The paromomycin glycosides retain activity against clin. strains of MRSA that are resistant to paromomycin, which is demonstrated to be a consequence of 4'-O-glycosylation blocking the action of 4'-aminoglycoside nucleotidyl transferases by the use of recombinant E. coli carrying the specific resistance determinant.
46
Sati, G. C., Shcherbakov, D., Hobbie, S., Vasella, A., Böttger, E. C., and Crich, D. (2017) N6′, N6‴, and O4′-Modifications to Neomycin Affect Ribosomal Selectivity Without Compromising Antibacterial Activity. ACS Infect. Dis. 3, 368– 376, DOI: 10.1021/acsinfecdis.6b00214
Google Scholar
46
N6', N6''', and O4' Modifications to Neomycin Affect Ribosomal Selectivity without Compromising Antibacterial Activity
Sati, Girish C.; Shcherbakov, Dimitri; Hobbie, Sven N.; Vasella, Andrea; Bottger, Erik C.; Crich, David
ACS Infectious Diseases (2017), 3 (5), 368-377CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)
The synthesis of a series of neomycin derivs. carrying the 2-hydroxyethyl substituent on N6' and/or N6''' both alone and in combination with a 4'-O-Et group is described. By means of cell-free translation assays with wild-type bacterial ribosomes and their hybrids with eukaryotic decoding A sites, we investigate how individual substituents and their combinations affect activity and selectivity at the target level. In principle, and as shown by cell-free translation assays, modifications of the N6' and N6''' positions allow to enhance target selectivity without compromising antibacterial activity. As with the 6'OH paromomycin, the 4'-O-Et modification further affects the ribosomal activity, selectivity, and antibacterial profile of neomycin and its 6'-N-(2-hydroxyethyl) derivs. The modified aminoglycosides show good antibacterial activity against model Gram-pos. and Gram-neg. microbes including the ESKAPE pathogens S. aureus, K. pneumoniae, E. cloacae, and A. baumannii.
47
Matsushita, T., Sati, G. C., Kondasinghe, N., Pirrone, M. G., Kato, T., Waduge, P., Kumar, H. S., Cortes Sanchon, A., Dobosz-Bartoszek, M., Shcherbakov, D., Juhas, M., Hobbie, S. N., Schrepfer, T., Chow, C. S., Polikanov, Y. S., Schacht, J., Vasella, A., Böttger, E. C., and Crich, D. (2019) Design, Multigram Synthesis, and in Vitro and in Vivo Evaluation of Propylamycin: A Semisynthetic 4,5-Deoxystreptamine Class Aminoglycoside for the Treatment of Drug-Resistant Enterobacteriaceae and Other Gram-Negative Pathogens. J. Am. Chem. Soc. 141, 5051– 5061, DOI: 10.1021/jacs.9b01693
Google Scholar
47
Design, Multigram Synthesis, and in Vitro and in Vivo Evaluation of Propylamycin: A Semisynthetic 4,5-Deoxystreptamine Class Aminoglycoside for the Treatment of Drug-Resistant Enterobacteriaceae and Other Gram-Negative Pathogens
Matsushita, Takahiko; Sati, Girish C.; Kondasinghe, Nuwan; Pirrone, Michael G.; Kato, Takayuki; Waduge, Prabuddha; Kumar, Harshitha Santhosh; Sanchon, Adrian Cortes; Dobosz-Bartoszek, Malgorzata; Shcherbakov, Dimitri; Juhas, Mario; Hobbie, Sven N.; Schrepfer, Thomas; Chow, Christine S.; Polikanov, Yury S.; Schacht, Jochen; Vasella, Andrea; Bottger, Erik C.; Crich, David
Journal of the American Chemical Society (2019), 141 (12), 5051-5061CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
Infectious diseases due to multidrug-resistant pathogens, particularly carbapenem-resistant Enterobacteriaceae (CREs), present a major and growing threat to human health and society, providing an urgent need for the development of improved potent antibiotics for their treatment. We describe the design and development of a new class of aminoglycoside antibiotics culminating in the discovery of propylamycin. Propylamycin is a 4'-deoxy-4'-alkyl paromomycin whose alkyl substituent conveys excellent activity against a broad spectrum of ESKAPE pathogens and other Gram-neg. infections, including CREs, in the presence of numerous common resistance determinants, be they aminoglycoside modifying enzymes or rRNA Me transferases. Importantly, propylamycin is demonstrated not to be susceptible to the action of the ArmA resistance determinant whose presence severely compromises the action of plazomicin and all other 4,6-disubstituted 2-deoxystreptamine aminoglycosides. The lack of susceptibility to ArmA, which is frequently encoded on the same plasmid as carbapenemase genes, ensures that propylamycin will not suffer from problems of cross-resistance when used in combination with carbapenems. Cell-free translation assays, quant. ribosome footprinting, and X-ray crystallog. support a model in which propylamycin functions by interference with bacterial protein synthesis. Cell-free translation assays with humanized bacterial ribosomes were used to optimize the selectivity of propylamycin, resulting in reduced ototoxicity in guinea pigs. In mouse thigh and septicemia models of Escherichia coli, propylamycin shows excellent efficacy, which is better than paromomycin. Overall, a simple novel deoxy alkyl modification of a readily available aminoglycoside antibiotic increases the inherent antibacterial activity, effectively combats multiple mechanisms of aminoglycoside resistance, and minimizes one of the major side effects of aminoglycoside therapy.
48
Böttger, E. C. and Schacht, J. (2013) The Mitochondrion: A Perpetrator of Acquired Hearing Loss. Hear. Res. 303, 12– 19, DOI: 10.1016/j.heares.2013.01.006
Google Scholar
48
The mitochondrion: A perpetrator of acquired hearing loss
Bottger, Erik C.; Schacht, Jochen
Hearing Research (2013), 303 (), 12-19CODEN: HERED3; ISSN:0378-5955. (Elsevier B.V.)
A review. Age, drugs, and noise are major causes of acquired hearing loss. The involvement of reactive oxygen species (ROS) in hair cell death has long been discussed, but there is considerably less information available as to the mechanisms underlying ROS formation. Most cellular ROS arise in mitochondria and this review will evaluate evidence for mitochondrial pathol. in general and dysfunction of the mitochondrial respiratory chain in particular in acquired hearing loss. We will discuss evidence that different pathways can lead to the generation of ROS and that oxidative stress might not necessarily be causal to all three pathologies. Finally, we will detail recent advances in exploiting knowledge of aminoglycoside-mitochondria interactions for the development of non-ototoxic antibacterials.This article is part of a Special Issue entitled "Annual Reviews 2013".
49
Huth, M. E., Ricci, A. J., and Cheng, A. G. (2011) Mechanisms of Aminoglycoside Ototoxicity and Targets of Hair Cell Protection. Int. J. Otolaryngol. 2011, 937861, DOI: 10.1155/2011/937861
Google Scholar
49
Mechanisms of aminoglycoside ototoxicity and targets of hair cell protection
Huth M E; Ricci A J; Cheng A G
International journal of otolaryngology (2011), 2011 (), 937861 ISSN:.
Aminoglycosides are commonly prescribed antibiotics with deleterious side effects to the inner ear. Due to their popular application as a result of their potent antimicrobial activities, many efforts have been undertaken to prevent aminoglycoside ototoxicity. Over the years, understanding of the antimicrobial as well as ototoxic mechanisms of aminoglycosides has increased. These mechanisms are reviewed in regard to established and potential future targets of hair cell protection.
50
Jiang, M., Karasawa, T., and Steyger, P. S. (2017) Aminoglycoside-Induced Cochleotoxicity: A Review. Front. Cell. Neurosci. 11, 308, DOI: 10.3389/fncel.2017.00308
Google Scholar
50
Aminoglycoside-induced cochleotoxicity: a review
Jiang, Meiyan; Karasawa, Takatoshi; Steyger, Peter S.
Frontiers in Cellular Neuroscience (2017), 11 (), 308/1-308/14CODEN: FCNRAH; ISSN:1662-5102. (Frontiers Media S.A.)
Aminoglycoside antibiotics are used as prophylaxis, or urgent treatment, for many life-threatening bacterial infections, including tuberculosis, sepsis, respiratory infections in cystic fibrosis, complex urinary tract infections and endocarditis. Although aminoglycosides are clin.-essential antibiotics, the mechanisms underlying their selective toxicity to the kidney and inner ear continue to be unraveled despite more than 70 years of investigation. The following mechanisms each contribute to aminoglycoside-induced toxicity after systemic administration: (1) drug trafficking across endothelial and epithelial barrier layers; (2) sensory cell uptake of these drugs; and (3) disruption of intracellular physiol. pathways. Specific factors can increase the risk of drug-induced toxicity, including sustained exposure to higher levels of ambient sound, and selected therapeutic agents such as loop diuretics and glycopeptides. Serious bacterial infections (requiring life-saving aminoglycoside treatment) induce systemic inflammatory responses that also potentiate the degree of ototoxicity and permanent hearing loss. We discuss prospective clin. strategies to protect auditory and vestibular function from aminoglycoside ototoxicity, including reduced cochlear or sensory cell uptake of aminoglycosides, and otoprotection by ameliorating intracellular cytotoxicity.
51
Cassinelli, G., Franceschi, G., Di Colo, G., and Arcamone, F. (1978) Semisynthetic Aminoglycoside Antibiotics 1. New Reactions of Paromomycin and Synthesis of its 2′-N-Ethyl Derivative. J. Antibiot. 31, 378– 381, DOI: 10.7164/antibiotics.31.379
Google Scholar
There is no corresponding record for this reference.
52
Cassinelli, G., Julita, P., and Arcamone, F. (1978) Semisynthetic Aminoglycoside Antibiotics II. Synthesis of Analogues of Paromomycin Modified in the Glucosamine Moiety. J. Antibiot. 31, 382– 384, DOI: 10.7164/antibiotics.31.382
Google Scholar
52
Semisynthetic aminoglycoside antibiotics. II. Synthesis of analogs of paromomycin modified in the glucosamine moiety
Cassinelli, Giuseppe; Julita, Piera; Arcamone, Federico
Journal of Antibiotics (1978), 31 (4), 382-4CODEN: JANTAJ; ISSN:0021-8820.
Aminoglycosides I, II, and III were prepd. from 1,3,2''',6'''-tetra-N-acetylparomomycin by a series of known reactions via IV as the key intermediate. Reaction of IV with dimer of 3,4-di-O-acetyl-2-deoxy-2-nitroso-6-O-tosyl-α-D-glucopyranosyl chloride led to I and II in 6 and 2% overall yield, resp. Reaction of IV with dimer of 3,4-di-O-acetyl-2-deoxy-2-nitroso-6-O-tosyl-α-D-galactopyranosyl chloride led to III in 4% overall yield. In comparison with the antibacterial activity of paromomycin, I showed similar or slightly reduced potency against sensitive organisms and a two-fold increased activity against some resistant strains of gram-neg. bacteria, while II and III showed a weak antibacterial activity.
53
Roestamadji, J., Graspsas, I., and Mobashery, S. (1995) Loss of Individual Electrostatic Interactions between Aminoglycoside Antibiotics and Resistance Enzymes as an Effective Means to Overcoming Bacterial Drug Resistance. J. Am. Chem. Soc. 117, 11060– 11069, DOI: 10.1021/ja00150a004
Google Scholar
53
Loss of individual electrostatic interactions between aminoglycoside antibiotics and resistance enzymes as an effective means to overcoming bacterial drug resistance
Roestamadji, Juliatiek; Grapsas, Ioannis; Mobashery, Shahriar
Journal of the American Chemical Society (1995), 117 (45), 11060-9CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
Aminoglycoside-modifying enzymes modify the structures of aminoglycoside antibiotics, rendering them ineffective, a process which confers resistance to the antibiotic. Electrostatic interactions (ion pairing and hydrogen bonding) are believed to be significant for both substrate recognition and catalysis by these enzymes. Regiospecific syntheses of 7 distinct deaminated analogs of neamine and kanamycin A (I, II, III, IV and V, VI, and VII, resp.), 2 aminoglycoside antibiotics, are described. Each of these compds. would have impaired interaction with a different subsite of the enzyme active sites. All 7 mols. were exceedingly poor substrates for 2 aminoglycoside-modifying enzymes, aminoglycoside 3'-phosphotransferases types Ia and IIa. The energetic contribution of interactions of the active-site functions with each of these amines on stabilization of the transition-state species has been evaluated to be in the range of 6-11 kcal/mol, the largest energy contribution recorded in the literature for such interactions. The biol. activities of these analogs were the same against the resistant organisms harboring aminoglycoside 3'-phosphotransferases types Ia and IIa as those against the background strain without the resistant enzymes. Thus, these compds. are virtually unmodified by those enzymes in vivo. The principles described here should be of general interest for circumvention of resistance to other antibiotics, by redesigning the structures to minimize electrostatic interactions with their corresponding resistance enzymes.
54
Ferrier, R. J., Hay, R. W., and Vethaviyasar, N. (1973) A Potentially Versatile Synthesis of Glycosides. Carbohydr. Res. 27, 55– 61, DOI: 10.1016/S0008-6215(00)82424-6
Google Scholar
54
Potentially versatile synthesis of glycosides
Ferrier, R. J.; Hay, R. W.; Vethaviyasar, N.
Carbohydrate Research (1973), 27 (1), 55-61CODEN: CRBRAT; ISSN:0008-6215.
Ph 1-thio-D-glucopyranosides in the presence of Hg(II) salts are readily solvolyzed to give alkyl D-glucopyranosides with inverted anomeric configuration. Methanolyses of the β and α anomers afford the Me α- and β-glycosides in yields of 74 and 87%, resp.; NMR examns. indicated that, whereas the β-glycoside was produced stereospecifically, the α-glycoside was formed together with ∼6% of its β isomer. The approach can be extended to the synthesis of complex glycosides as was illustrated by the prepn. of cholestanyl and 1-naphthyl α-D-glucopyranoside and a disaccharide deriv.
55
Greenberg, W. A., Priestley, E. S., Sears, P. S., Alper, P. B., Rosenbohm, C., Hendrix, M., Hung, S.-C., and Wong, C.-H. (1999) Design and Synthesis of New Aminoglycoside Antibiotics Containing Neamine as an Optimal Core Structure: Correlation of Antibiotic Activity with in Vitro Inhibition of Translation. J. Am. Chem. Soc. 121, 6527– 6541, DOI: 10.1021/ja9910356
Google Scholar
55
Design and Synthesis of New Amino Glycoside Antibiotics Containing Neamine as an Optimal Core Structure: Correlation of Antibiotic Activity with in Vitro Inhibition of Translation
Greenberg, William A.; Priestley, E. Scott; Sears, Pamela S.; Alper, Phil B.; Rosenbohm, Christoph; Hendrix, Martin; Hung, Shang-Cheng; Wong, Chi-Huey
Journal of the American Chemical Society (1999), 121 (28), 6527-6541CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
The structure and activity of the pseudo-disaccharide core found in amino glycoside antibiotics was probed with a series of synthetic analogs in which the position of amino groups was varied around the glucopyranose ring. The naturally occurring structure neamine was the best in the series according to assays for in vitro RNA binding and antibiotic activity. With this result in hand, neamine was used as a common core structure for the synthesis of new antibiotics, which were evaluated for binding to models of the Escherichia coli 16S A-site rRNA, in vitro protein synthesis inhibition, and antibiotic activity. Anal. of RNA binding revealed some correlation between the relative affinity and specificity of RNA binding and antibacterial efficacy. However, the correlation was not linear. This result led us to develop the in vitro translation assay in an effort to better understand amino glycoside-RNA interactions. A linear correlation between in vitro translation inhibition and antibiotic activity was obsd. In addn., IC50s in the protein synthesis assay were typically lower than the Kds obtained for RNA binding, suggesting that binding of these compds. to intact ribosomes is tighter in these cases than binding to the model RNA oligodeoxyribonucleotides. This reflects possible differences in RNA conformation between intact ribosomes and the free RNA of the model system, or possible high-affinity ribosomal binding sites in addn. to the A-site RNA.
56
Lu, S.-R., Lai, Y. H., Chen, J.-H., Liu, C.-Y., and Mong, K.-K. T. (2011) Dimethylformamide: An Unusual Glycosylation Modulator. Angew. Chem., Int. Ed. 50, 7315– 7320, DOI: 10.1002/anie.201100076
Google Scholar
56
Dimethylformamide: An Unusual Glycosylation Modulator
Lu, Shao-Ru; Lai, Yen-Hsun; Chen, Jiun-Han; Liu, Chih-Yueh; Mong, Kwok-Kong Tony
Angewandte Chemie, International Edition (2011), 50 (32), 7315-7320, S7315/1-S7315/125CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
When N,N-dimethylformamide was used to direct the stereochem. course of glycosylation reactions, 1,2-cis glycosylation products were formed with excellent selectivity. A straightforward highly α-stereoselective glycosylation involving preactivation should find broad application and be esp. useful for sequential glycosylation reactions to form oligosaccharides.
57
Saegusa, T., Kobayashi, S., Ito, Y., and Yasuda, N. (1968) Radical Reaction of Isocyanide with Organotin Hydride. J. Am. Chem. Soc. 90, 4182– 4182, DOI: 10.1021/ja01017a061
Google Scholar
57
Radical reaction of isocyanide with organotin hydride
Saegusa, Takeo; Kobayashi, Shiro; Ito, Yoshihiko; Yasuda, Naohiko
Journal of the American Chemical Society (1968), 90 (15), 4182CODEN: JACSAT; ISSN:0002-7863.
Isocyanides (RNC) and trialkyltin hydrides gave trialkyltin isocyanides and the hydrocarbon RH. In a typical reaction, PhCH2NC, Bu3SnH, and tert-Bu2O2 under N gave Bu3Sn (iso)cyanide, identical with the product from Bu3SnCl and KCN. A free radical mechanism is proposed.
58
Barton, D. H. R., Bringmann, G., Lamotte, G., Motherwell, W. B., Hay Motherwell, R. S., and Porter, A. E. A. (1980) Reactions of Relevance to the Chemistry of the Aminoglycoside Antibiotics. Part 14. A Useful Radical-Deamination Reaction. J. Chem. Soc., Perkin Trans. 1 1, 2657– 2664, DOI: 10.1039/p19800002657
Google Scholar
There is no corresponding record for this reference.
59
Barton, D. H. R., Bringmann, G., and Motherwell, W. B. (1980) Reactions of Relevance to the Aminoglycoside Antibiotics. Part 15. The Selective Modification of Neamine by Radical-Induced Deamination. J. Chem. Soc., Perkin Trans. 1 1, 2665– 2669, DOI: 10.1039/p19800002665
Google Scholar
There is no corresponding record for this reference.
60
Ballestri, M., Chatgilialoglu, C., Clark, K. B., Griller, D., Giese, B., and Kopping, B. (1991) Tris(trimethylsily1)silane as a Radical-Based Reducing Agent in Synthesis. J. Org. Chem. 56, 678– 683, DOI: 10.1021/jo00002a035
Google Scholar
60
Tris(trimethylsilyl)silane as a radical-based reducing agent in synthesis
Ballestri, M.; Chatgilialoglu, C.; Clark, K. B.; Griller, D.; Giese, B.; Kopping, B.
Journal of Organic Chemistry (1991), 56 (2), 678-83CODEN: JOCEAH; ISSN:0022-3263.
Tris(trimethylsilyl)silane is an effective reducing agent for org. halides, selenides, xanthates, and isocyanides, as well as an effective hydrosilylating agent for dialkyl ketones and alkenes. The silane functions as a mediator in the formation of intermol. carbon-carbon bonds via radicals and allows a variety of org. substrates to be used as alkyl radical precursors. Abs. rate consts. for the reaction of (Me3Si)3Si• radicals with a variety of org. compds. were measured in soln. by laser flash photolysis. At 294 K rate consts. are >5 × 107M-1 s-1 for C:C double bonds that are activated by neighboring π-electron systems or by electron-withdrawing groups. For other substrates, reactivities decreased in order xanthate > selenide > isocyanide > nitro > sulfide.
61
Goddard-Borger, E. D. and Stick, R. V. (2007) An Efficient, Inexpensive, and Shelf-Stable Diazotransfer Reagent: Imidazole-1-sulfonyl Azide Hydrochloride. Org. Lett. 9, 3797– 3800, DOI: 10.1021/ol701581g
Google Scholar
61
An Efficient, Inexpensive, and Shelf-Stable Diazotransfer Reagent: Imidazole-1-sulfonyl Azide Hydrochloride
Goddard-Borger, Ethan D.; Stick, Robert V.
Organic Letters (2007), 9 (19), 3797-3800CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
The design and synthesis of a new diazotransfer reagent, imidazole-1-sulfonyl azide hydrochloride, are reported. This reagent has proven to equal triflyl azide in its ability to act as a "diazo donor" in the conversion of both primary amines into azides and activated methylene substrates into diazo compds. Crucially, this reagent can be prepd. in a one-pot reaction on a large scale from inexpensive materials, is shelf-stable, and is conveniently cryst.
62
Ye, H., Liu, R., Li, D., Liu, Y., Yuan, H., Guo, W., Zhou, L., Cao, X., Tian, H., Shen, J., and Wang, P. G. (2013) A Safe and Facile Route to Imidazole-1-sulfonyl Azide as a Diazotransfer Reagent. Org. Lett. 15, 18– 21, DOI: 10.1021/ol3028708
Google Scholar
62
A Safe and Facile Route to Imidazole-1-sulfonyl Azide as a Diazotransfer Reagent
Ye, Hui; Liu, Ruihua; Li, Dongmei; Liu, Yonghui; Yuan, Haixin; Guo, Weikang; Zhou, Lifei; Cao, Xuefeng; Tian, Hongqi; Shen, Jie; Wang, Peng George
Organic Letters (2013), 15 (1), 18-21CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
A facile approach to the diazo-transfer reagent of imidazole-1-sulfonyl azide was reported. The procedure was well optimized to clarify potential explosion risks. A high prodn. yield as well as small batch variation was achieved even without careful pretreatment of reagents and solvents. HPLC and NMR methods to monitor the process were provided. These features made this protocol suitable for large scale prepn. in academia and industry as well.
63
Fischer, N., Goddard-Borger, E. D., Greiner, R., Klapotke, T. M., Skelton, B. W., and Stierstorfer, J. (2012) Senstivities of Some Imidazole-1-sulfonyl Azide Salts. J. Org. Chem. 77, 1760– 1764, DOI: 10.1021/jo202264r
Google Scholar
63
Sensitivities of Some Imidazole-1-sulfonyl Azide Salts
Fischer, Niko; Goddard-Borger, Ethan D.; Greiner, Robert; Klapoetke, Thomas M.; Skelton, Brian W.; Stierstorfer, Joerg
Journal of Organic Chemistry (2012), 77 (4), 1760-1764CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
Imidazole-1-sulfonyl azide hydrochloride, an inexpensive and effective diazo transfer reagent, was recently found to be impact sensitive. To identify safer-to-handle forms of this reagent, several different salts of imidazole-1-sulfonyl azide were prepd., and their sensitivity to heat, impact, friction, and electrostatic discharge was quant. detd. A no. of these salts exhibited improved properties and can be considered safer than the aforementioned hydrochloride. The solid-state structures of the chloride and less sensitive hydrogen sulfate were detd. by single-crystal x-ray diffraction in an effort to provide some insight into the different properties of the materials.
64
Potter, G. T., Jayson, G. C., Miller, G. J., and Gardiner, J. M. (2016) An Updated Synthesis of the Diazo-Transfer Reagent Imidazole-1-sulfonyl Azide Hydrogen Sulfate. J. Org. Chem. 81, 3443– 3446, DOI: 10.1021/acs.joc.6b00177
Google Scholar
64
An Updated Synthesis of the Diazo-Transfer Reagent Imidazole-1-sulfonyl Azide Hydrogen Sulfate
Potter, Garrett T.; Jayson, Gordon C.; Miller, Gavin J.; Gardiner, John M.
Journal of Organic Chemistry (2016), 81 (8), 3443-3446CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
Imidazole-1-sulfonyl azide and salts thereof are valuable reagents for diazo-transfer reactions, most particularly conversion of primary amines to azides. The parent reagent and its HCl salt present stability and detonation risks, but the hydrogen sulfate salt is significantly more stable. An updated procedure for the large-scale synthesis of this salt avoids isolation or concn. of the parent compd. or HCl salt and will facilitate the use of hydrogen sulfate salt as the reagent of choice for diazo transfer.
65
Flynn, D. L., Zelle, R. E., and Grieco, P. A. (1983) A Mild Two-Step Method for the Hydolysis/Methanolysis of Secondary Amides and Lactams. J. Org. Chem. 48, 2424– 2426, DOI: 10.1021/jo00162a028
Google Scholar
65
A mild two-step method for the hydrolysis of lactams and secondary amides
Flynn, Daniel L.; Zelle, Robert E.; Grieco, Paul A.
Journal of Organic Chemistry (1983), 48 (14), 2424-6CODEN: JOCEAH; ISSN:0022-3263.
We report herein that N-tert-Boc derivs. of lactams and amides, prepd. through the agency of di-tert-Bu dicarbonate, suffer regioselective hydrolysis employing LiOH or methanolysis under mild conditions leading to the corresponding ω-amino acids or esters, resp. N-(tert-Butoxycarbonyl)-γ-butyrolactam was stirred with LiOH at 25° and the mixt. was acidified to give Me3COC(O)NH(CH2)3CO2H.
66
Pathak, R., Perez-Fernandez, D., Nandurdikar, R., Kalapala, S. K., Böttger, E. C., and Vasella, A. (2008) Synthesis and Evaluation of Paromomycin Derivatives Modified at C(4′). Helv. Chim. Acta 91, 1533– 1552, DOI: 10.1002/hlca.200890167
Google Scholar
66
Synthesis and evaluation of paromomycin derivatives modified at C(4')
Pathak, Rashmi; Perez-Fernandez, Deborah; Nandurdikar, Rahul; Kalapala, Sarath K.; Bottger, Erik C.; Vasella, Andrea
Helvetica Chimica Acta (2008), 91 (8), 1533-1552CODEN: HCACAV; ISSN:0018-019X. (Verlag Helvetica Chimica Acta)
The 2-amino-2-deoxy-α-D-glucopyranosyl moiety (ring I) of paromomycin was replaced by a 2,4-diamino-2,4-dideoxy-α-D-glucopyranosyl, 2,4-diamino-2,4-dideoxy-α-D-galactopyranosyl, 2-amino-2-deoxy-α-D-galactopyranosyl, or 3,4,5-trideoxy-4-aza-α-D-erythro-heptoseptanosyl moiety to investigate the effect of the substituent at C(4') on the interaction with rRNA. Thus, title oligosaccharide I was prepd. from paromomycin via azidolysis, Dess-Martin's oxidn., stereoselective redn., periodate bond cleavage, azide redn., and debenzylation reactions. The derivs. possessing a D-galacto-configured ring I, e.g. I ( R = NH2, OH, R1 = H), were less active than the corresponding D-gluco-analogs and paromomycin. The C(4')-aminodeoxy deriv. I (R = H, R1 = NH2) (D-gluco ring I) and the known 4'-deoxyparomomycin, prepd. by a new route, displayed slightly lower antibacterial activities than paromomycin. Cell-wall permeability is not responsible for the unexpectedly low activity for oligosaccharide I (R = H, R1 = NH2), as shown by cell-free translation assays. The results evidence that the orientation of the substituent at C(4') is more important than its nature for drug binding and activity.
67
Schmitz, J., Li, T., Bartz, U., and Gütschow, M. (2016) Cathepsin B Inhibitors: Combining Dipeptide Nitriles with an Occluding Loop Recognition Element by Click Chemistry. ACS Med. Chem. Lett. 7, 211– 216, DOI: 10.1021/acsmedchemlett.5b00474
Google Scholar
67
Cathepsin B Inhibitors: Combining Dipeptide Nitriles with an Occluding Loop Recognition Element by Click Chemistry
Schmitz, Janina; Li, Tianwei; Bartz, Ulrike; Guetschow, Michael
ACS Medicinal Chemistry Letters (2016), 7 (3), 211-216CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
An active site mapping of human cathepsin B with dipeptide nitrile inhibitors was performed for a combinatorial approach by introducing several points of diversity and stepwise optimizing the inhibitor structure. To address the occluding loop of cathepsin B by a carboxylate moiety, click chem. to generate linker-connected mols. was applied. Inhibitor (S,S)-N-(4-phenylbenzoyl)-3-bromophenylalanyl-O-((1-(carboxymethyl)-1H-1,2,3-triazol-4-yl)methyl)serine nitrile (compd. 17) exhibited Ki values of 41.3 nM, 27.3 nM, or 19.2 nM, depending on the substrate and pH of the assay. Kinetic data were discussed with respect to the conformational selection and induced fit models.
68
LaPlanche, L. A. and Rogers, M. T. (1964) cis and trans Configurations of the Peptide Bond in N-Monosubstituted Amides by Nuclear Magnetic Resonance. J. Am. Chem. Soc. 86, 337– 341, DOI: 10.1021/ja01057a007
Google Scholar
68
Cis and trans configurations of the peptide bond in N-monosubstituted amides by nuclear magnetic resonance
LaPlanche, Laurine A.; Rogers, Max T.
Journal of the American Chemical Society (1964), 86 (3), 337-41CODEN: JACSAT; ISSN:0002-7863.
The nuclear magnetic resonance spectra of 13 N-monosubstituted aliphatic amides show that N-methylformamide, N-ethylformamide, N-isopropylformamide, and N-tert-butylformamide exist in both the cis and the trans configuration about the central C.sbd.N bond. Although the trans form predominates, the % cis isomer increases as the N substituent becomes more bulky. Studies of the change in chem. shift of the N substituent on diln. with benzene are in accord with the peak assignments. Spin coupling consts. between the protons on C and N may be found for each isomer in H2SO4 solns. of the formamides. The remaining 9 amides, where the carbonyl substituent was larger than H, showed the presence of only the trans configuration.
69
Fowler, P., Bernet, B., and Vasella, A. (1996) A ¹H-NMR Spectroscopic Investigation of the Conformation of the Acetamido Group in Some Derivatives of N-Acetyl-D-allosamine and D-Glucosamine. Helv. Chim. Acta 79, 269– 287, DOI: 10.1002/hlca.19960790127
Google Scholar
69
A 1H-NMR spectroscopic investigation of the conformation of the acetamide group in some derivatives of N-acetyl-D-allosamine and -D-glucosamine
Fowler, Paul; Bernet, Bruno; Vasella, Andrea
Helvetica Chimica Acta (1996), 79 (1), 269-87CODEN: HCACAV; ISSN:0018-019X. (Verlag Helvetica Chimica Acta)
The population of the conformations obtained by rotation around the C(2)-N and the N-C(O) bonds of AllNAc, GlcNAc, and GlcNMeAc derivs. was investigated by 1H-NMR spectroscopy. The AllNAc-derived α-D- and β-D-pyranosides I [R or R1 = OMe, OCHMe2, OCH(CF3)2, OC6H4NO2], the AllNAc diazirine I (RR1 = N:N), and the GlcNAc-derived axial anomers II [R = OMe, OCH(CF3)2, OC6H4NO2; R1 = R3 = H; R2 = PhCH2] prefer the (Z)-anti-conformation. A significant population of the (Z)-syn-conformer in the (Z)-syn/(Z)-anti-equil. for the equatorial anomers and the GlcNAc diazirine II (RR1 = N:N; R2 = PhCH2; R3 = H; III) was evidenced by an upfield shift of H-C(2), downfield shifts of H-C(1) and H-C(3), and by NOE measurements. The population of the (Z)-syn-conformation depends on the substituent at C(1) and is highest for the hexafluoroisopropyl glycoside. The population of the (Z)-syn conformation depends on the substituent at C(1) and H-C(3), and by NOE measurements. The population of the (Z)-syn-conformation depends on the substituent at C(1) and is highest for the hexafluoroisopropyl glycoside. The population of the (Z)-syn-conformation of β-D-II (R = OMe; R1 = R3 = H; R2 = Me) decreases with increasing polarity of the solvent, but a substantial population is still obsd. for solns. in D2O. Whereas the α-D-anomers II (R = R2 = R3 = H; R1 = OMe or H) prefer the (Z)-anti-conformation in D2O soln., the corresponding β-D-anomers are mixts. of the (Z)-anti- and (Z)-sym-conformers. The diazirine III self-assocs. in CD2Cl2 soln. at concns. >0.005 M at low temps. The axial anomers II (R = H; R1 = OMe; R2 = H, Me, PhCH2; R3 = Me) are 2:1 to 3:1 mixts. of (Z)-anti- and (E)-anti-conformers whereas the corresponding β-D-glycosides are ca. 1:3:6 mixts. of (Z)-syn-, (Z)-anti-, and (E)-anti-conformers.
70
Hu, X., Zhang, W., Carmichael, I., and Serianni, A. S. (2010) Amide Cis-Trans Isomerization in Aqueous Solutions of Methyl N-Formyl-D-glucosaminides and Methyl N-Acetyl-D-glucosaminides: Chemical Equilibria and Exchange Kinetics. J. Am. Chem. Soc. 132, 4641– 4652, DOI: 10.1021/ja9086787
Google Scholar
70
Amide Cis-Trans Isomerization in Aqueous Solutions of Methyl N-Formyl-D-glucosaminides and Methyl N-Acetyl-D-glucosaminides: Chemical Equilibria and Exchange Kinetics
Hu, Xiaosong; Zhang, Wenhui; Carmichael, Ian; Serianni, Anthony S.
Journal of the American Chemical Society (2010), 132 (13), 4641-4652CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
Amide cis-trans isomerization (CTI) in Me 2-deoxy-2-acylamido-D-glucopyranosides was investigated by 1H and 13C NMR spectroscopy. Singly 13C-labeled Me 2-deoxy-2-formamido-D-glucopyranoside (MeGlcNFm) anomers provided std. 1H and 13C chem. shifts and 1H-1H and 13C-13C spin-coupling consts. for cis and trans amides that are detected readily in aq. soln. Equipped with this information, doubly 13C-labeled Me 2-deoxy-2-acetamido-D-glucopyranoside (MeGlcNAc) anomers were investigated, leading to the detection and quantification of cis and trans amides in this biol. important aminosugar. In comparison to MeGlcNFm anomers, the percentage of cis amide in aq. solns. of MeGlcNAc anomers is small (∼23% for MeGlcNFm vs. ∼1.8% for MeGlcNAc at 42 °C) but nevertheless observable with assistance from 13C-labeling. Temp. studies gave thermodn. parameters ΔG°, ΔH°, and ΔS° for cis-trans interconversion in MeGlcNFm and MeGlcNAc anomers. Cis/trans equil. depended on anomeric configuration, with solns. of α-anomers contg. less cis amide than those of β-anomers. Confirmation of the presence of cis amide in MeGlcNAc solns. derived from quant. 13C satn. transfer measurements of CTI rate consts. as a function of soln. temp., yielding activation parameters Eact, ΔG°⧧, ΔH°⧧, and ΔS°⧧ for saccharide CTI. Rate consts. for the conversion of trans to cis amide in MeGlcNFm and MeGlcNAc anomers ranged from 0.02 to 3.59 s-1 over 31-85 °C, compared to 0.24-80 s-1 for the conversion of cis to trans amide over the same temp. range. Energies of activation ranged from 16-19 and 19-20 kcal/mol for the cis → trans and trans → cis processes, resp. Complementary DFT calcns. on MeGlcNFm and MeGlcNAc model structures were conducted to evaluate the effects of an acyl side chain and anomeric structure, as well as C2-N2 bond rotation, on CTI energetics. These studies show that aq. solns. of GlcNAc-contg. structures contain measurable amts. of both cis and trans amides, which may influence their biol. properties.
71
Naito, T., Nakagawa, S., Narita, Y., and Kawaguchi, H. (1976) Chemical Modification of Sorbistin. N-Acyl Analogs of Sorbistin. J. Antibiot. 29, 1286– 1296, DOI: 10.7164/antibiotics.29.1286
Google Scholar
71
Chemical modification of sorbistin. I. N-acyl analogs of sorbistin
Naito, Takayuki; Nakagawa, Susumu; Narita, Yukio; Kawaguchi, Hiroshi
Journal of Antibiotics (1976), 29 (12), 1286-96CODEN: JANTAJ; ISSN:0021-8820.
Sorbistin A1 I (R = COEt) (II) and sorbistin B1 I (R = COMe) produced by Pseudomonas were converted into III by blocking the 1- and 4-amino groups with dimedone and subsequent deacylation of the 4'-N-acyl group. 4'-N-acyl analogs of sorbistin were prepd. by 4'-N-acylation of III by the mixed anhydride, acid chloride, or activated ester methods, followed by deblocking with Br2 or NaNO2. Sorbistins I (R = COMe, COPr) and II were interconverted by this method. Acyl derivs. of sorbistin D I (R = H), were prepd. In vitro antimicrobial activity showed that I (R = cyclopropylcarbonyl) and II were most active. Elongation and shortening of the side chain and introduction of functional groups decreased the activity. N-acylation of the N-1 or N-4 amino groups gave inactive products.
72
Hanessian, S., Takamoto, T., and Masse, R. (1975) Oxidative Degradations Leading to Novel Biochemical Probes and Synthetic Intermediates. J. Antibiot. 28, 835– 836, DOI: 10.7164/antibiotics.28.835
Google Scholar
72
Aminoglycoside antibiotics. Oxidative degradations leading to novel biochemical probes and synthetic intermediates
Hanessian, Stephen; Takamoto, Tetsuyoshi; Masse, Robert
Journal of Antibiotics (1975), 28 (10), 835-7CODEN: JANTAJ; ISSN:0021-8820.
I [R = H (II), 2,6-diamino-2,6-dideoxy-α-D-glucopyranosyl (III)] were prepd. by sequential HIO4 oxidn. and β-eliminative degrdn. of paromomycin and neomycin B, resp. II was devoid of antibacterial activity whereas III had 4-10 times less activity than neamine.
73
Pathak, R., Böttger, E. C., and Vasella, A. (2005) Design and Synthesis of Aminoglycoside Antibiotics to Selectively Target 16S Ribosomal RNA Position 1408. Helv. Chim. Acta 88, 2967– 2984, DOI: 10.1002/hlca.200590240
Google Scholar
73
Design and synthesis of amino glycoside antibiotics to selectively target 16S ribosomal RNA position 1408
Pathak, Rashmi; Bottger, Erik C.; Vasella, Andrea
Helvetica Chimica Acta (2005), 88 (11), 2967-2985CODEN: HCACAV; ISSN:0018-019X. (Verlag Helvetica Chimica Acta)
The glucopyranosyl moiety (ring I) of paromomycin was modified in a search for novel amino-glycoside antibiotics, e.g. I•5CF3COOH, via regioselective fluoro-dehydroxylation and reductive fragmentation reactions. As compared to paromomycin, the C(6')-deoxy and fluoro-deoxy derivs., e.g. I•5CF3COOH, showed a lower activity against both wild type 1408A and 1408G mutant ribosomes.
74
Fukami, H., Ikeda, S., Kitahara, K., and Nakajima, M. (1977) Total Synthesis of Ribostamycin. Agric. Biol. Chem. 41, 1689– 1694, DOI: 10.1271/bbb1961.41.1689
Google Scholar
74
Synthetic studies on carbohydrate antibiotics. XVIII. Total synthesis of ribostamycin
Fukami, Harukazu; Ikeda, Shoji; Kitahara, Katsuhiko; Nakajima, Minoru
Agricultural and Biological Chemistry (1977), 41 (9), 1689-94CODEN: ABCHA6; ISSN:0002-1369.
Suitably protected 5-O-β-D-ribofuranosyl-2-deoxystreptamine was condensed with protected 2,6-diamino-2,6-dideoxy-α-D-glucopyranosyl bromide by a modified Koenigs-Knorr reaction to give 3 condensation products, one of which was confirmed as a ribostamycin deriv. The others were designated as its 6-O-α- and 6-O-β-isomers by the PMR spectra of their free bases and N-acetyl derivs. and by their chem. reactions.
75
Carter, A. P., Clemons, W. M., Brodersen, D. E., Morgan-Warren, R. J., Wimberly, B. T., and Ramakrishnan, V. (2000) Functional Insights from the Structure of the 30S Ribosomal Subunit and its Interactions with Antibiotics. Nature 407, 340– 348, DOI: 10.1038/35030019
Google Scholar
75
Functional insights from the structure of the 30S ribosomal subunit and its interactions with antibiotics
Carter, Andrew P.; Clemons, William M.; Brodersen, Ditlev E.; Morgan-Warren, Robert J.; Wimberly, Brian T.; Ramakrishnan, V.
Nature (London) (2000), 407 (6802), 340-348CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
The 30S ribosomal subunit has two primary functions in protein synthesis. It discriminates against aminoacyl tRNAs that do not match the codon of mRNA, thereby ensuring accuracy in translation of the genetic message in a process called decoding. Also, it works with the 50S subunit to move the tRNAs and assocd. mRNA by precisely one codon, in a process called translocation. Here we describe the functional implications of the high-resoln. 30S crystal structure presented in the accompanying paper, and infer details of the interactions between the 30S subunit and its tRNA and mRNA ligands. We also describe the crystal structure of the 30S subunit complexed with the antibiotics paromomycin, streptomycin and spectinomycin, which interfere with decoding and translocation. This work reveals the structural basis for the action of these antibiotics, and leads to a model for the role of the universally conserved 16S RNA residues A1492 and A1493 in the decoding process.
76
Hobbie, S. N., Kalapala, S. K., Akshay, S., Bruell, C., Schmidt, S., Dabow, S., Vasella, A., Sander, P., and Böttger, E. C. (2007) Engineering the rRNA Decoding Site of Eukaryotic Cytosolic Ribosomes in Bacteria. Nucleic Acids Res. 35, 6086– 6093, DOI: 10.1093/nar/gkm658
Google Scholar
76
Engineering the rRNA decoding site of eukaryotic cytosolic ribosomes in bacteria
Hobbie, Sven N.; Kalapala, Sarath K.; Akshay, Subramanian; Bruell, Christian; Schmidt, Sebastian; Dabow, Sabine; Vasella, Andrea; Sander, Peter; Boettger, Erik C.
Nucleic Acids Research (2007), 35 (18), 6086-6093CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
Structural and genetic studies on prokaryotic ribosomes have provided important insights into fundamental aspects of protein synthesis and translational control and its interaction with ribosomal drugs. Comparable mechanistic studies in eukaryotes are mainly hampered by the absence of both high-resoln. crystal structures and efficient genetic models. To study the interaction of aminoglycoside antibiotics with selected eukaryotic ribosomes, we replaced the bacterial drug binding site in 16S rRNA with its eukaryotic counterpart, resulting in bacterial hybrid ribosomes with a fully functional eukaryotic rRNA decoding site. Cell-free translation assays demonstrated that hybrid ribosomes carrying the rRNA decoding site of higher eukaryotes show pronounced resistance to aminoglycoside antibiotics, equiv. to that of rabbit reticulocyte ribosomes, while the decoding sites of parasitic protozoa show distinctive drug susceptibility. Our findings suggest that phylogenetically variable components of the ribosome, other than the rRNA-binding site, do not affect aminoglycoside susceptibility of the protein-synthesis machinery. The activities of the hybrid ribosomes indicate that helix 44 of the rRNA decoding site behaves as an autonomous domain, which can be exchanged between ribosomes of different phylogenetic domains for study of function.
77
Hobbie, S. N., Akshay, S., Kalapala, S. K., Bruell, C., Shcherbakov, D., and Böttger, E. C. (2008) Genetic Analysis of Interactions with Eukaryotic rRNA Identify the Mitoribosome as Target in Aminoglycoside Ototoxicity. Proc. Natl. Acad. Sci. U. S. A. 105, 20888– 20893, DOI: 10.1073/pnas.0811258106
Google Scholar
77
Genetic analysis of interactions with eukaryotic rRNA identify the mitoribosome as target in aminoglycoside ototoxicity
Hobbie, Sven N.; Akshay, Subramanian; Kalapala, Sarath K.; Bruell, Christian M.; Shcherbakov, Dmitry; Bottger, Eric C.
Proceedings of the National Academy of Sciences of the United States of America (2008), 105 (52), 20888-20893CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
Aminoglycoside ototoxicity has been related to a surprisingly large no. of cellular structures and metabolic pathways. The finding that patients with mutations in mitochondrial rRNA are hypersusceptible to aminoglycoside-induced hearing loss has indicated a possible role for mitochondrial protein synthesis. To study the mol. interaction of aminoglycosides with eukaryotic ribosomes, we made use of the observation that the drug binding site is a distinct domain defined by the small subunit rRNA, and investigated drug susceptibility of bacterial hybrid ribosomes carrying various alleles of the eukaryotic decoding site. Compared to hybrid ribosomes with the A site of human cytosolic ribosomes, susceptibility of mitochondrial hybrid ribosomes to various aminoglycosides correlated with the relative cochleotoxicity of these drugs. Sequence alterations that correspond to the mitochondrial deafness mutations A1555G and C1494T increased drug-binding and rendered the ribosomal decoding site hypersusceptible to aminoglycoside-induced mistranslation and inhibition of protein synthesis. Our results provide exptl. support for aminoglycoside-induced dysfunction of the mitochondrial ribosome. We propose a pathogenic mechanism in which interference of aminoglycosides with mitochondrial protein synthesis exacerbates the drugs' cochlear toxicity, playing a key role in sporadic dose-dependent and genetically inherited, aminoglycoside-induced deafness.
78
Hobbie, S. N., Bruell, C. M., Akshay, S., Kalapala, S. K., Shcherbakov, D., and Böttger, E. C. (2008) Mitochondrial Deafness Alleles Confer Misreading of the Genetic Code. Proc. Natl. Acad. Sci. U. S. A. 105, 3244– 3249, DOI: 10.1073/pnas.0707265105
Google Scholar
78
Mitochondrial deafness alleles confer misreading of the genetic code
Hobbie, Sven N.; Bruell, Christian M.; Akshay, Subramanian; Kalapala, Sarath K.; Shcherbakov, Dmitry; Bottger, Erik C.
Proceedings of the National Academy of Sciences of the United States of America (2008), 105 (9), 3244-3249CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
Despite the fact that important genetic diseases are caused by mutant mitochondrial ribosomes, the mol. mechanisms by which such ribosomes result in a clin. phenotype remain largely unknown. The absence of exptl. models for mitochondrial diseases has also prevented the rational search for therapeutic interventions. Here, we report on the construction of bacterial hybrid ribosomes that contain various versions of the mitochondrial decoding region of rRNA. We show that the pathogenic mutations A1555G and C1494T decrease the accuracy of translation and render the ribosomal decoding site hypersusceptible to aminoglycoside antibiotics. This finding suggests misreading of the genetic code as an important mol. mechanism in disease pathogenesis.
79
Hobbie, S. N., Kaiser, M., Schmidt, S., Shcherbakov, D., Janusic, T., Brun, R., and Böttger, E. C. (2011) Genetic Reconstruction of Protozoan rRNA Decoding Sites Provides a Rationale for Paromomycin Activity against Leishmania and Trypanosoma. PLoS Neglected Trop. Dis. 5, e1161 DOI: 10.1371/journal.pntd.0001161
Google Scholar
79
Genetic reconstruction of protozoan rRNA decoding sites provides a rationale for paromomycin activity against Leishmania and Trypanosoma
Hobbie, Sven N.; Kaiser, Marcel; Schmidt, Sebastian; Shcherbakov, Dmitri; Janusic, Tanja; Brun, Reto; Bottger, Erik C.
PLoS Neglected Tropical Diseases (2011), 5 (5), e1161CODEN: PNTDAM; ISSN:1935-2735. (Public Library of Science)
Aminoglycoside antibiotics target the ribosomal decoding A-site and are active against a broad spectrum of bacteria. These compds. bind to a highly conserved stem-loop-stem structure in helix 44 of bacterial 16S rRNA. One particular aminoglycoside, paromomycin, also shows potent antiprotozoal activity and is used for the treatment of parasitic infections, e.g. by Leishmania spp. The precise drug target is, however, unclear; in particular whether aminoglycoside antibiotics target the cytosolic and/or the mitochondrial protozoan ribosome. To establish an exptl. model for the study of protozoan decoding-site function, we constructed bacterial chimeric ribosomes where the central part of bacterial 16S rRNA helix 44 has been replaced by the corresponding Leishmania and Trypanosoma rRNA sequences. Relating the results from in vitro ribosomal assays to that of in vivo aminoglycoside activity against Trypanosoma brucei, as assessed in cell cultures and in a mouse model of infection, we conclude that aminoglycosides affect cytosolic translation while the mitochondrial ribosome of trypanosomes is not a target for aminoglycoside antibiotics.
80
Qian, Y. and Guan, M.-X. (2009) Interaction of Aminoglycosides with Human Mitochondrial 12S rRNA Carrying the Deafness-Associated Mutation. Antimicrob. Agents Chemother. 53, 4612– 4618, DOI: 10.1128/AAC.00965-08
Google Scholar
80
Interaction of aminoglycosides with human mitochondrial 12S rRNA carrying the deafness-associated mutation
Qian, Yaping; Guan, Min-Xin
Antimicrobial Agents and Chemotherapy (2009), 53 (11), 4612-4618CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
The mitochondrial 12S rRNA A1555G mutation is one of the important causes of aminoglycoside-induced and nonsyndromic hearing loss. Here the authors employed an RNA-directed chem.-modification approach to understanding the pathogenesis of aminoglycoside-induced hearing loss. The patterns of chem. modification of RNA oligonucleotides carrying the A1555G mutation by di-Me sulfate (DMS) were distinct from those of the RNA oligonucleotides carrying wild-type sequence in the presence of aminoglycosides. In the RNA analog carrying the A1555G mutation, reduced reactivity to DMS occurred in base G1555 as well as in bases C1556 and A1553 in the presence of paromomycin, neomycin, gentamicin, kanamycin, tobramycin, or streptomycin. In particular, base G1555 exhibited marked but similar levels of protection in the presence of 0.1 μM to 100 μM neomycin, gentamicin, or kanamycin. In contrast, the levels of protection in base G1555 appeared to be correlated with the concn. of paromycin, tobramycin, or streptomycin. Furthermore, increasing reactivities to DMS in the presence of these aminoglycosides were obsd. for bases A1492, C1493, C1494, and A1557 in the RNA analog carrying the A1555G mutation. These data suggested that the A1555G mutation altered the binding properties of aminoglycosides at the A site of 12S rRNA and led to local conformational changes in 12S rRNA carrying the A1555G mutation. The interaction between aminoglycosides and 12S rRNA carrying the A1555G mutation provides new insight into the pathogenesis of aminoglycoside ototoxicity.
81
Prezant, T. R., Agapian, J. V., Bohlman, M. C., Bu, X., Öztas, S., Qiu, W.-Q., Arnos, K. S., Cortopassi, G. A., Jaber, L., Rotter, J. I., Shohat, M., and Fischel-Ghodsian, N. (1993) Mitochondrial Ribosomal RNA Mutation Associated with Both Antibiotic-Induced and Non-Syndromic Deafness. Nat. Genet. 4, 289– 294, DOI: 10.1038/ng0793-289
Google Scholar
81
Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness
Prezant, Toni R.; Agapian, John V.; Bohlman, M. Charlotte; Bu, Xiangdong; Oztas, Sitki; Qiu, Wei Qin; Arnos, Kathleen S.; Cortopassi, Gino A.; Jaber, Lutfi; et al.
Nature Genetics (1993), 4 (3), 289-94CODEN: NGENEC; ISSN:1061-4036.
Maternally transmitted non-syndromic deafness was described recently both in pedigrees with susceptibility to aminoglycoside ototoxicity and in a large Arab-Israeli pedigree. Because of the known action of aminoglycosides on bacterial ribosomes, the authors analyzed the sequence of mitochondrial rRNA genes of three unrelated patients with familial aminoglycoside-induced deafness. The authors also sequenced the complete mitochondrial genome of the Arab-Israeli pedigree. All four families shared a nucleotide 1555 A to G substitution in the 12S rRNA gene, a site implicated in aminoglycoside activity. This study offers the first description of a mitochondrial rRNA mutation leading to disease, the first cases of non-syndromic deafness caused by a mitochondrial DNA mutation and the first mol. genetic study of antibiotic-induced ototoxicity.
82
Tadanier, J., Martin, J. R., Johnson, P., Goldstein, A. W., and Hallas, R. (1980) 2′-N-Acylfortimicins and 2′-N-Alkylfortimicins via the Isofortimicin Rearrangement. Carbohydr. Res. 85, 61– 71, DOI: 10.1016/S0008-6215(00)84564-4
Google Scholar
82
2'-N-Acylfortimicins and 2'-N-alkylfortimicins via the isofortimicin rearrangement
Tadanier, Jack; Martin, Jerry R.; Johnson, Paulette; Goldstein, Alma W.; Hallas, Robert
Carbohydrate Research (1980), 85 (1), 61-71CODEN: CRBRAT; ISSN:0008-6215.
Fortimicin A and a no. of 4-N-acylfortimicins B, although stable as either the fully protonated hydrochloride or sulfate salts, undergo degrdn. as the free bases in aq. soln. Detailed studies with fortimicin A and 4-N-acetylfortimicin B show that degrdn. occurs, in part, by simple cleavage of the 4-N-acyl groups with formation of fortimicin B, and, in part, by rearrangement to the 2'-N-acylfortimicins B (the isofortimicin rearrangement). The conversions of the rearrangement products into 2'-N-glycylfortimicin A, 2'-N-acetylfortimicin A, and the 2'-N-(2-aminoethyl)fortimicins A and B are described. The antibacterial activities of the new fortimicin A derivs. were less than that of fortimicin A.
83
Satoi, S., Awata, M., Muto, N., Hayashi, M., Sagai, H., and Otani, M. (1983) A New Aminoglycoside Antibiotic G-367 S₁, 2′-N-Formylsisomicin. Fermentation, Isolation and Characterization. J. Antibiot. 36, 1– 5, DOI: 10.7164/antibiotics.36.1
Google Scholar
83
A new aminoglycoside antibiotic G-367 S1, 2'-N-formylsisomicin. Fermentation, isolation and characterization
Satoi, Shuzo; Awata, Masashi; Muto, Naoki; Hayashi, Mitsuo; Sagai, Hitoshi; Otani, Masaru
Journal of Antibiotics (1983), 36 (1), 1-5CODEN: JANTAJ; ISSN:0021-8820.
A new aminoglycoside antibiotic, G-367 S1 (I) produced by a rare actinomycete, Dactylosporangium thailandense G-367 (FERM-P 4840) was isolated by column chromatog. on a cation-exchange resin. G-367 S1 is active against gram-pos. and gram-neg. bacteria.
84
Wong, C.-H., Hendrix, M., Manning, D. D., Rosenbohm, C., and Greenberg, A. A. (1998) A Library Approach to the Discovery of Small Molecules That Recognize RNA: Use of a 1,3-Hydroxyamine Motif as Core. J. Am. Chem. Soc. 120, 8319– 8327, DOI: 10.1021/ja980826p
Google Scholar
84
A Library Approach to the Discovery of Small Molecules That Recognize RNA: Use of a 1,3-Hydroxyamine Motif as Core
Wong, Chi-Huey; Hendrix, Martin; Manning, David D.; Rosenbohm, Christoph; Greenberg, William A.
Journal of the American Chemical Society (1998), 120 (33), 8319-8327CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
A library of compds. based upon an amino-glucopyranoside core has been developed and screened for binding to RNA and specifically to 16S rRNA. The title mols. simplify the complexity of naturally occurring aminoglycoside antibiotics by embodying a putative recognition motif found within these structures, namely, a 1,3-hydroxyamine. The core pyranoside bearing the hydroxyamine motif was structurally varied at two points through a combinatorial approach utilizing acylation and reductive amination protocols. The aminoglycoside mimetics were screened in an automated assay based upon surface plasmon resonance (SPR), and some were found effective at binding a 27-nucleotide model (AS-wt) of A-site 16S RNA as well as a drug-resistant mutant RNA in the micro-molar range.
85
Nessar, R., Cambau, E., Reyrat, J. M., Murray, A., and Gicquel, B. (2012) Mycobacterium abscessus: A New Antibiotic Nightmare. J. Antimicrob. Chemother. 67, 810– 818, DOI: 10.1093/jac/dkr578
Google Scholar
85
Mycobacterium abscessus: A new antibiotic nightmare
Nessar, Rachid; Cambau, Emmanuelle; Reyrat, Jean Marc; Murray, Alan; Gicquel, Brigitte
Journal of Antimicrobial Chemotherapy (2012), 67 (4), 810-818CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
A review. The intrinsic and acquired resistance of Mycobacterium abscessus to commonly used antibiotics limits the chemotherapeutic options for infections caused by these mycobacteria. Intrinsic resistance is attributed to a combination of the permeability barrier of the complex multilayer cell envelope, drug export systems, antibiotic targets with low affinity and enzymes that neutralize antibiotics in the cytoplasm. To date, acquired resistance has only been obsd. for aminoglycosides and macrolides, which is conferred by mutations affecting the genes encoding the antibiotic targets (rrs and rrl, resp.). Here, the authors summarize previous and recent findings on the resistance of M. abscessus to antibiotics in light of what has been discovered for other mycobacteria. Since we can now distinguish three groups of strains belonging to M. abscessus (M. abscessus sensu stricto, Mycobacterium massiliense and Mycobacterium bolletii), studies on antibiotic susceptibility and resistance should be considered according to this new classification. This review raises the profile of this important pathogen and highlights the work needed to decipher the mol. events responsible for its extensive chemotherapeutic resistance.
86
Maurer, F. P., Bruderer, V. L., Castelberg, C., Ritter, C., Scherbakov, D., Bloemberg, G. V., and Böttger, E. C. (2015) Aminoglycoside-modifying Enzymes Determine the Innate Susceptibility to Aminoglycoside Antibiotics in Rapidly Growing Mycobacteria. J. Antimicrob. Chemother. 70, 1412– 1419, DOI: 10.1093/jac/dku550
Google Scholar
86
Aminoglycoside-modifying enzymes determine the innate susceptibility to aminoglycoside antibiotics in rapidly growing mycobacteria
Maurer, Florian P.; Bruderer, Vera L.; Castelberg, Claudio; Ritter, Claudia; Scherbakov, Dimitri; Bloemberg, Guido V.; Bottger, Erik C.
Journal of Antimicrobial Chemotherapy (2015), 70 (5), 1412-1419CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
Infections caused by the rapidly growing mycobacterium (RGM) Mycobacterium abscessus are notoriously difficult to treat due to the innate resistance of M. abscessus to most clin. available antimicrobials. Aminoglycoside antibiotics (AGA) are a cornerstone of antimicrobial chemotherapy against M. abscessus infections, although little is known about intrinsic drug resistance mechanisms. The authors investigated the role of chromosomally encoded putative aminoglycoside-modifying enzymes (AME) in AGA susceptibility in M. abscessus. Clin. isolates of M. abscessus were tested for susceptibility to a series of AGA with different substituents at positions 2', 3' and 4' of ring 1 in MIC assays. Cell-free exts. of M. abscessus type strain ATCC 19977 and Mycobacterium smegmatis strains SZ380 [aac(2')-Id+], EP10 [aac(2')-Id-] and SZ461 [aac(2')-Id+, rrs A1408G] were investigated for AGA acetylation activity using thin-layer chromatog. (TLC). Cell-free ribosome translation assays were performed to directly study drug-target interaction. Cell-free translation assays demonstrated that ribosomes of M. abscessus and M. smegmatis show comparable susceptibility to all tested AGA. MIC assays for M. abscessus and M. smegmatis, however, consistently showed the lowest MIC values for 2'-hydroxy-AGA as compared with 2'-amino-AGA, indicating that an aminoglycoside-2'-acetyltransferase, Aac(2'), contributes to innate AGA susceptibility. TLC expts. confirmed enzymic activity consistent with Aac(2'). Using M. smegmatis as a model for RGM, acetyltransferase activity was shown to be up-regulated in response to AGA-induced inhibition of protein synthesis. The findings point to AME as important determinants of AGA susceptibility in M. abscessus.
87
François, B., Russell, R. J. M., Murray, J. B., Aboul-Ela, F., Masquid, B., Vicens, Q., and Westhof, E. (2005) Crystal Structures of Complexes Between Aminoglycosides and Decoding A Site Oligonucleotides: Role of the Number of Rings and Positive Charges in the Specific Binding Leading to Miscoding. Nucleic Acids Res. 33, 5677– 5690, DOI: 10.1093/nar/gki862
Google Scholar
87
Crystal structures of complexes between aminoglycosides and decoding A site oligonucleotides: role of the number of rings and positive charges in the specific binding leading to miscoding
Francois, Boris; Russell, Rupert J. M.; Murray, James B.; Aboul-ela, Fareed; Masquida, Benoit; Vicens, Quentin; Westhof, Eric
Nucleic Acids Research (2005), 33 (17), 5677-5690CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
The crystal structures of six complexes between aminoglycoside antibiotics (neamine, gentamicin C1A, kanamycin A, ribostamycin, lividomycin A and neomycin B) and oligonucleotides contg. the decoding A site of bacterial ribosomes are reported at resolns. between 2.2 and 3.0 Å. Although the no. of contacts between the RNA and the aminoglycosides varies between 20 and 31, up to eight direct hydrogen bonds between rings I and II of the neamine moiety are conserved in the obsd. complexes. The puckered sugar ring I is inserted into the A site helix by stacking against G1491 and forms a pseudo base pair with two H-bonds to the Watson-Crick sites of the universally conserved A1408. This central interaction helps to maintain A1492 and A1493 in a bulged-out conformation. All these structures of the minimal A site RNA complexed to various aminoglycosides display crystal packings with intermol. contacts between the bulging A1492 and A1493 and the shallow/minor groove of Watson-Crick pairs in a neighboring helix. In one crystal, one empty A site is obsd. In two crystals, two aminoglycosides are bound to the same A site with one bound specifically and the other bound in various ways in the deep/major groove at the edge of the A sites.
88
Kaul, M. and Pilch, D. S. (2002) Thermodynamics of Aminoglycoside-rRNA Recognition: The Binding of Neomycin-Class Aminoglycosides to the A Site of 16S rRNA. Biochemistry 41, 7695– 7706, DOI: 10.1021/bi020130f
Google Scholar
88
Thermodynamics of Aminoglycoside-rRNA Recognition: The Binding of Neomycin-Class Aminoglycosides to the A Site of 16S rRNA
Kaul, Malvika; Pilch, Daniel S.
Biochemistry (2002), 41 (24), 7695-7706CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
We use spectroscopic and calorimetric techniques to characterize the binding of the aminoglycoside antibiotics neomycin, paromomycin, and ribostamycin to a RNA oligonucleotide that models the A-site of Escherichia coli 16S rRNA. Our results reveal the following significant features: (i) Aminoglycoside binding enhances the thermal stability of the A-site RNA duplex, with the extent of this thermal enhancement decreasing with increasing pH and/or Na+ concn. (ii) The RNA binding enthalpies of the aminoglycosides become more exothermic (favorable) with increasing pH, an observation consistent with binding-linked protonation of one or more drug amino groups. (iii) Isothermal titrn. calorimetry (ITC) studies conducted as a function of buffer reveal that aminoglycoside binding to the host RNA is linked to the uptake of protons, with the no. of linked protons being dependent on pH. Specifically, increasing the pH results in a corresponding increase in the no. of linked protons. (iv) ITC studies conducted at 25 and 37° reveal that aminoglycoside-RNA complexation is assocd. with a neg. heat capacity change (ΔCp), the magnitude of which becomes greater with increasing pH. (v) The obsd. RNA binding affinities of the aminoglycosides decrease with increasing pH and/or Na+ concn. In addn., the thermodn. forces underlying these RNA binding affinities also change as a function of pH. Specifically, with increasing pH, the enthalpic contribution to the obsd. RNA binding affinity increases, while the corresponding entropic contribution to binding decreases. (vi) The affinities of the aminoglycosides for the host RNA follow the hierarchy neomycin > paromomycin > ribostamycin. The enhanced affinity of neomycin relative to either paromomycin or ribostamycin is primarily, if not entirely, enthalpic in origin. (vii) The salt dependencies of the RNA binding affinities of neomycin and paromomycin are consistent with at least three drug NH3+ groups participating in electrostatic interactions with the host RNA. In the aggregate, our results reveal the impact of specific alterations in aminoglycoside structure on the thermodn. of binding to an A-site model RNA oligonucleotide. Such systematic comparative studies are crit. first steps toward establishing the thermodn. database required for enhancing our understanding of the mol. forces that dictate and control aminoglycoside recognition of RNA.
89
Kaul, M., Barbieri, C. M., Kerrigan, J. E., and Pilch, D. S. (2003) Coupling of Drug Protonation to the Specific Binding of Aminoglycosides to the A Site of 16 S rRNA: Elucidation of the Number of Drug Amino Groups Involved and their Identities. J. Mol. Biol. 326, 1373– 1387, DOI: 10.1016/S0022-2836(02)01452-3
Google Scholar
89
Coupling of Drug Protonation to the Specific Binding of Aminoglycosides to the A Site of 16 S rRNA: Elucidation of the Number of Drug Amino Groups Involved and their Identities
Kaul, Malvika; Barbieri, Christopher M.; Kerrigan, John E.; Pilch, Daniel S.
Journal of Molecular Biology (2003), 326 (5), 1373-1387CODEN: JMOBAK; ISSN:0022-2836. (Elsevier Science Ltd.)
2-Deoxystreptamine (2-DOS) aminoglycoside antibiotics bind specifically to the central region of the 16 S rRNA A site and interfere with protein synthesis. Recently, we have shown that the binding of 2-DOS aminoglycosides to an A site model RNA oligonucleotide is linked to the protonation of drug amino groups. Here, we extend these studies to define the no. of amino groups involved as well as their identities. Specifically, we use pH-dependent 15N NMR spectroscopy to det. the pKa values of the amino groups in neomycin B, paromomycin I, and lividomycin A sulfate, with the resulting pKa values ranging from 6.92 to 9.51. For each drug, the 3-amino group was assocd. with the lowest pKa, with this value being 6.92 in neomycin B, 7.07 in paromomycin I, and 7.24 in lividomycin A. In addn., we use buffer-dependent isothermal titrn. calorimetry (ITC) to det. the no. of protons linked to the complexation of the three drugs with the A site model RNA oligomer at pH 5.5, 8.8, or 9.0. At pH 5.5, the binding of the three drugs to the host RNA is independent of drug protonation effects. By contrast, at pH 9.0, the RNA binding of paromomycin I and neomycin B is coupled to the uptake of 3.25 and 3.80 protons, resp., with the RNA binding of lividomycin A at pH 8.8 being coupled to the uptake of 3.25 protons. A comparison of these values with the protonation states of the drugs predicted by our NMR-derived pKa values allows us to identify the specific drug amino groups whose protonation is linked to complexation with the host RNA. These detns. reveal that the binding of lividomycin A to the host RNA is coupled to the protonation of all five of its amino groups, with the RNA binding of paromomycin I and neomycin B being linked to the protonation of four and at least five amino groups, resp. For paromomycin I, the protonation reactions involve the 1-, 3-, 2'-, and 2'''-amino groups, while, for neomycin B, the binding-linked protonation reactions involve at least the 1-, 3-, 2', 6'-, and 2'''-amino groups. Our results clearly identify drug protonation reactions as important thermodn. participants in the specific binding of 2-DOS aminoglycosides to the A site of 16 S rRNA.
90
Wasserman, M. R., Pulk, A., Zhou, Z., Altman, R. B., Zinder, J. C., Green, K. D., Garneau-Tsodikova, S., Doudna Cate, J. H., and Blanchard, S. C. (2015) Chemically Related 4,5-Linked Aminoglycoside Antibiotics Drive Subunit Rotation in Opposite Directions. Nat. Commun. 6, 7896, DOI: 10.1038/ncomms8896
Google Scholar
90
Chemically related 4,5-linked aminoglycoside antibiotics drive subunit rotation in opposite directions
Wasserman, Michael R.; Pulk, Arto; Zhou, Zhou; Altman, Roger B.; Zinder, John C.; Green, Keith D.; Garneau-Tsodikova, Sylvie; Doudna Cate, Jamie H.; Blanchard, Scott C.
Nature Communications (2015), 6 (), 7896CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)
Dynamic remodelling of intersubunit bridge B2, a conserved RNA domain of the bacterial ribosome connecting helixes 44 (h44) and 69 (H69) of the small and large subunit, resp., impacts translation by controlling intersubunit rotation. Here we show that aminoglycosides chem. related to neomycin-paromomycin, ribostamycin and neamine-each bind to sites within h44 and H69 to perturb bridge B2 and affect subunit rotation. Neomycin and paromomycin, which only differ by their ring-I 6'-polar group, drive subunit rotation in opposite directions. This suggests that their distinct actions hinge on the 6'-substituent and the drug's net pos. charge. By solving the crystal structure of the paromomycin-ribosome complex, we observe specific contacts between the apical tip of H69 and the 6'-hydroxyl on paromomycin from within the drug's canonical h44-binding site. These results indicate that aminoglycoside actions must be framed in the context of bridge B2 and their regulation of subunit rotation.
91
Vacas, T., Corzana, F., Jiménez-Osés, G., González, C., Gómez, A. M., Bastida, A., Revuelta, J., and Asensio, J. L. (2010) Role of Aromatic Rings in the Molecular Recognition of Aminoglycoside Antibiotics: Implications for Drug Design. J. Am. Chem. Soc. 132, 12074– 12090, DOI: 10.1021/ja1046439
Google Scholar
91
Role of Aromatic Rings in the Molecular Recognition of Aminoglycoside Antibiotics: Implications for Drug Design
Vacas, Tatiana; Corzana, Francisco; Jimenez-Oses, Gonzalo; Gonzalez, Carlos; Gomez, Ana M.; Bastida, Agatha; Revuelta, Julia; Asensio, Juan Luis
Journal of the American Chemical Society (2010), 132 (34), 12074-12090CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
Aminoglycoside antibiotics participate in a large variety of binding processes involving both RNA and proteins. The description, in recent years, of several clin. relevant aminoglycoside/receptor complexes has greatly stimulated the structural-based design of new bioactive derivs. Unfortunately, design efforts have frequently met with limited success, reflecting our incomplete understanding of the mol. determinants for the antibiotic recognition. Intriguingly, arom. rings of the protein/RNA receptors seem to be key actors in this process. Indeed, close inspection of the structural information available reveals that they are frequently involved in CH/π stacking interactions with sugar/amino-cyclitol rings of the antibiotic. While the interaction between neutral carbohydrates and arom. rings has been studied in detail during past decade, little is known about these contacts when they involve densely charged glycosides. Herein we report a detailed exptl. and theor. anal. of the role played by CH/π stacking interactions in the mol. recognition of amino-glycosides. Our study aims to det. the influence that the antibiotic poly-cationic character has on the stability, preferred geometry, and dynamics of these particular contacts. With this purpose, different aminoglycoside/arom. complexes have been selected as model systems. They varied from simple bimol. interactions to the more stable intramol. CH/π contacts present in designed derivs. The obtained results highlight the key role played by electrostatic forces and the de-solvation of charged groups in the mol. recognition of poly-cationic glycosides and have clear implications for the design of improved antibiotics.
92
Hanessian, S., Saavedra, O. M., Vilchis-Reyes, M. A., Maianti, J. P., Kanazawa, H., Dozzo, P., Matias, R. D., Serio, A., and Kondo, J. (2014) Synthesis, Broad Spectrum Antibacterial Activity, and X-ray Co-crystal Structure of the Decoding Bacterial Ribosomal A-Site with 4′-Deoxy-4′-Fluoro Neomycin Analogs. Chem. Sci. 5, 4621– 4632, DOI: 10.1039/C4SC01626B
Google Scholar
92
Synthesis, broad spectrum antibacterial activity, and X-ray co-crystal structure of the decoding bacterial ribosomal A-site with 4'-deoxy-4'-fluoro neomycin analogs
Hanessian, S.; Saavedra, O. M.; Vilchis-Reyes, M. A.; Maianti, J. P.; Kanazawa, H.; Dozzo, P.; Matias, R. D.; Serio, A.; Kondo, J.
Chemical Science (2014), 5 (12), 4621-4632CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
This study reports the synthesis, antibacterial evaluation and nature of fluorine-rRNA contacts revealed by an X-ray co-crystal structure of a series of 4'-deoxy-4'-fluoro B-neomycin analogs. 4'-Deoxyfluorination improves the inhibition profile towards resistant enzymes and renders equally potent antibiotics compared to the parent neomycin B. The 4'-deoxy-4'-fluoro-4'-epi neomycin analogs showed a preferential inhibition over the 4'-deoxy-4'-fluoro neomycin counterpart against the strains of P. aeruginosa carrying a chromosomal APH(3')-IIb enzyme, known to inactivate the parent aminoglycoside. To the best of our knowledge, this is the first example of a neighboring-group aminoglycoside-modifying enzyme evasion by fluorine substitution. A unique F-G1491 stacking was obsd. in a co-crystal structure of 4'-deoxy-4'-fluoro-4'-epi neomycin with a bacterial rRNA A-site.
93
Hermann, T. and Westhof, E. (1999) Docking of Cationic Antibiotics to Negatively Charged Pockets in RNA Folds. J. Med. Chem. 42, 1250– 1261, DOI: 10.1021/jm981108g
Google Scholar
93
Docking of Cationic Antibiotics to Negatively Charged Pockets in RNA Folds
Hermann, Thomas; Westhof, Eric
Journal of Medicinal Chemistry (1999), 42 (7), 1250-1261CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
The binding of aminoglycosides to RNA provides a paradigm system for the anal. of RNA-drug interactions. The electrostatic field around three-dimensional RNA folds creates localized and defined neg. charged regions which are potential docking sites for the cationic ammonium groups of aminoglycosides. To explore in RNA folds the electroneg. pockets suitable for aminoglycoside binding, we used calcns. of the electrostatic field and Brownian dynamics simulations of cation diffusion. We applied the technique on those RNA mols. exptl. known to bind aminoglycosides, namely, two tobramycin aptamers: the aminoglycoside-binding region in 16S rRNA and the TAR RNA from human immunodeficiency virus. For the aptamers and rRNA, for which the binding sites of the aminoglycosides are known, a good agreement between neg. charged pockets and the binding positions of the drugs was found. On the basis of variations between neomycin-like and kanamycin-like aminoglycosides in the interaction with the electrostatic field of rRNA, we propose a model for the different binding specificities of these two classes of drugs. The spatial congruence between the electroneg. pockets in RNA folds and binding positions of aminoglycosides was used to dock aminoglycosides to ribosomal and TAR RNAs. Mol. dynamics simulations were used to analyze possible RNA-drug interactions. Aminoglycosides inhibit the binding of the viral Tat protein to TAR RNA; however, the drug-binding sites are still unknown. Thus, our docking approach provides first structural models for TAR-aminoglycoside complexes. The RNA-drug interactions obsd. in the modeled complexes support the view that the antibiotics might lock TAR in a conformation with low affinity for the Tat protein, explaining the exptl. found aminoglycoside inhibition of the Tat-TAR interaction.
94
Corzana, F., Cuesta, I., Freire, F., Revuelta, J., Torrado, M., Bastida, A., Jiménez-Barbero, J., and Asensio, J. L. (2007) The Pattern of Distribution of Amino Groups Modulates the Structure and Dynamics of Natural Aminoglycosides: Implications for RNA Recognition. J. Am. Chem. Soc. 129, 2849– 2865, DOI: 10.1021/ja066348x
Google Scholar
94
The Pattern of Distribution of Amino Groups Modulates the Structure and Dynamics of Natural Aminoglycosides: Implications for RNA Recognition
Corzana, Francisco; Cuesta, Igor; Freire, Felix; Revuelta, Julia; Torrado, Mario; Bastida, Agatha; Jimenez-Barbero, Jesus; Asensio, Juan Luis
Journal of the American Chemical Society (2007), 129 (10), 2849-2865CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
Aminoglycosides are clin. relevant antibiotics that participate in a large variety of mol. recognition processes involving different RNA and protein receptors. The 3-D structures of these polycationic oligosaccharides play a key role in RNA binding and therefore det. their biol. activity. Herein, the authors show that the particular NH2/NH3+/OH distribution within the antibiotic scaffold modulates the oligosaccharide conformation and flexibility. In particular, those polar groups flanking the glycosidic linkages have a significant influence on the antibiotic structure. A careful NMR/theor. anal. of different natural aminoglycosides, their fragments, and synthetic derivs. proves that both hydrogen bonding and charge-charge repulsive interactions are at the origin of this effect. Current strategies to obtain new aminoglycoside derivs. are mainly focused on the optimization of the direct ligand/receptor contacts. The results strongly suggest that the particular location of the NH2/NH3+/OH groups within the antibiotics can also modulate their RNA binding properties by affecting the conformational preferences and inherent flexibility of these drugs. This fact should also be carefully considered in the design of new antibiotics with improved activity.
95
Fourmy, D., Recht, M. I., Blanchard, S. C., and Puglisi, J. D. (1996) Structure of the A Site of Escherichia coli 16S Ribosomal RNA Complexed with an Aminoglycoside Antibiotic. Science 274, 1367– 1371, DOI: 10.1126/science.274.5291.1367
Google Scholar
95
Structure of the A site of Escherichia coli 16S ribosomal RNA complexed with an aminoglycoside antibiotic
Fourmy, Dominique; Recht, Michael I.; Blanchard, Scott C.; Puglisi, Joseph D.
Science (Washington, D. C.) (1996), 274 (5291), 1367-1371CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
Aminoglycoside antibiotics that bind to 30S ribosomal A-site RNA cause misreading of the genetic code and inhibit translocation. The aminoglycoside antibiotic paromomycin (I) binds specifically to an RNA oligonucleotide that contains the 30S subunit A site, and the soln. structure of the RNA-I complex was detd. by NMR spectroscopy. The antibiotic binds in the major groove of the model A-site RNA within a pocket created by an A-A base pair and a single bulged adenine. Specific interactions occur between aminoglycoside chem. groups important for antibiotic activity and conserved nucleotides in the RNA. The structure explains binding of diverse aminoglycosides to the ribosome, their specific activity against prokaryotic organisms, and various resistance mechanisms, and provides insight into ribosome function.
96
Zhao, F., Zhao, Q., Blount, K. F., Han, Q., Tor, Y., and Hermann, T. (2005) Moelcular Recognition of RNA by Neomycin and a Restricted Neomycin Derivative. Angew. Chem., Int. Ed. 44, 5329– 5334, DOI: 10.1002/anie.200500903
Google Scholar
96
Molecular recognition of RNA by neomycin and a restricted neomycin derivative
Zhao, Fang; Zhao, Qiang; Blount, Kenneth F.; Han, Qing; Tor, Yitzhak; Hermann, Thomas
Angewandte Chemie, International Edition (2005), 44 (33), 5329-5334CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
The preorganized presentation of functional groups in the antibiotic neomycin (green) is exploited to obtain a conformationally restricted aminoglycoside (yellow) by regioselective intramol. cyclization. X-ray crystallog. data show how the natural product and the deriv. recognize the RNA target motif that is the binding site of aminoglycoside antibiotics.
97
Blount, K. F., Zhao, F., Hermann, T., and Tor, Y. (2005) Conformational Constraint as a Means for Understanding RNA-Aminoglycoside Specificity. J. Am. Chem. Soc. 127, 9818– 9829, DOI: 10.1021/ja050918w
Google Scholar
97
Conformational Constraint as a Means for Understanding RNA-Aminoglycoside Specificity
Blount, Kenneth F.; Zhao, Fang; Hermann, Thomas; Tor, Yitzhak
Journal of the American Chemical Society (2005), 127 (27), 9818-9829CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
The lack of high RNA target selectivity displayed by aminoglycoside antibiotics results from both their electrostatically driven binding mode and their conformational adaptability. The inherent flexibility around their glycosidic bonds allows them to easily assume a variety of conformations, permitting them to structurally adapt to diverse RNA targets. This structural promiscuity results in the formation of aminoglycoside complexes with diverse RNA targets in which the antibiotics assume distinct conformations. Such differences suggest that covalently linking individual rings in an aminoglycoside could reduce its available conformations, thereby altering target selectivity. To explore this possibility, conformationally constrained neomycin and paromomycin analogs designed to mimic the A-site bound aminoglycoside structure have been synthesized and their affinities to the TAR and A-site, two therapeutically relevant RNA targets, have been evaluated. As per design, this constraint has minimal deleterious effect on binding to the A-site. Surprisingly, however, preorganizing these neomycin-class antibiotics into a TAR-disfavored structure has no deleterious effect on binding to this HIV-1 RNA sequence. The authors rationalize these observations by suggesting that the A-site and HIV TAR possess inherently different selectivities toward aminoglycosides. The inherent plasticity of the TAR RNA, coupled to the remaining flexibility within the conformationally constrained analogs, makes this RNA site an accommodating target for such polycationic ligands. In contrast, the deeply encapsulating A-site is a more discriminating RNA target. These observations suggest that future design of novel target selective RNA-based therapeutics will have to consider the inherent "structural" selectivity of the RNA target and not only the selectivity patterns displayed by the low mol. wt. ligands.
98
Asensio, J. L., Hidalgo, A., Bastida, A., Torrado, M., Corzana, F., Chiara, J. L., Garcia-Junceda, E., Cañada, J., and Jiménez-Barbero, J. (2005) A Simple Structural-Based Approach to Prevent Aminoglycoside Inactivation by Bacterial Defense Proteins. Conformational Restriction Provides Effective Protection against Neomycin-B Nucleotidylation by ANT. J. Am. Chem. Soc. 127, 8278– 8279, DOI: 10.1021/ja051722z
Google Scholar
98
A Simple Structural-Based Approach to Prevent Aminoglycoside Inactivation by Bacterial Defense Proteins. Conformational Restriction Provides Effective Protection against Neomycin-B Nucleotidylation by ANT4
Asensio, Juan Luis; Hidalgo, Ana; Bastida, Agatha; Torrado, Mario; Corzana, Francisco; Chiara, Jose Luis; Garcia-Junceda, Eduardo; Canada, Javier; Jimenez-Barbero, Jesus
Journal of the American Chemical Society (2005), 127 (23), 8278-8279CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
Herein, the authors describe how the conformational differences exhibited by aminoglycosides in the binding pockets of the ribosome and those enzymes involved in bacterial resistance can be exploited in the design of new antibiotic derivs. with improved activity in resistant strains. The simple modification shown in the figure, leading to the conformationally restricted 5, provides an effective protection against aminoglycoside inactivation by Staphylococcus aureus ANT4, both in vivo and in vitro.
99
Bastida, A., Hidalgo, A., Chiara, J. L., Torrado, M., Corzana, F., Pérez-Cañadillas, J. M., Groves, P., Garcia-Junceda, E., Gonzalez, C., Jimenez-Barbero, J., and Asensio, J. L. (2006) Exploring the Use of Conformationally Locked Aminoglycosides as a New Strategy to Overcome Bacterial Resistance. J. Am. Chem. Soc. 128, 100– 116, DOI: 10.1021/ja0543144
Google Scholar
99
Exploring the Use of Conformationally Locked Amino-Glycosides as a New Strategy to Overcome Bacterial Resistance
Bastida, Agatha; Hidalgo, Ana; Chiara, Jose Luis; Torrado, Mario; Corzana, Francisco; Perez-Canadillas, Jose Manuel; Groves, Patrick; Garcia-Junceda, Eduardo; Gonzalez, Carlos; Jimenez-Barbero, Jesus; Asensio, Juan Luis
Journal of the American Chemical Society (2006), 128 (1), 100-116CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
The emergence of bacterial resistance to the major classes of antibiotics has become a serious problem over recent years. For amino-glycosides, the major biochem. mechanism for bacterial resistance is the enzymic modification of the drug. Interestingly, in several cases, the oligosaccharide conformation recognized by the ribosomic RNA and the enzymes responsible for the antibiotic inactivation is remarkably different. This observation suggests a possible structure-based chem. strategy to overcome bacterial resistance; in principle, it should be possible to design a conformationally locked oligosaccharide that still retains antibiotic activity but that is not susceptible to enzymic inactivation. To explore the scope and limitations of this strategy, we have synthesized several amino-glycoside derivs. locked in the ribosome-bound "bioactive" conformation. The effect of the structural pre-organization on RNA binding, together with its influence on the amino-glycoside inactivation by several enzymes involved in bacterial resistance, has been studied. Our results indicate that the conformational constraint has a modest effect on their interaction with rRNA. In contrast, it may display a large impact on their enzymic inactivation. Thus, the work presented herein provides a key example of how the conformational differences exhibited by these ligands within the binding pockets of the ribosome and of those enzymes involved in bacterial resistance can, in favorable cases, be exploited for designing new antibiotic derivs. with improved activity in resistant strains.
100
Revuelta, J., Vacas, T., Bastida, A., and Asensio, J. L. (2010) Structure-Based Design of Highly Crowded Ribostamycin/Kananmycin Hybrids as a New Family of Antibiotics. Chem. - Eur. J. 16, 2986– 2991, DOI: 10.1002/chem.200903003
Google Scholar
100
Structure-Based Design of Highly Crowded Ribostamycin/Kanamycin Hybrids as a New Family of Antibiotics
Revuelta, Julia; Vacas, Tatiana; Corzana, Francisco; Gonzalez, Carlos; Bastida, Agatha; Asensio, Juan Luis
Chemistry - A European Journal (2010), 16 (10), 2986-2991, S2986/1-S2986/8CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
The 2-deoxystreptamine (2-DOS) ring of aminoglycoside pseudodisaccharide fragment I/II was modified with a neutral ribose (ring IV) unit and pyranose unit (xylosamine and glucose, ring III) at positions 5 and 6 of the 2-DOS ring, resp., providing hybrids between the 4,5- and 4,6-DOS subfamilies. The resultant pseudotetrasaccharides and natural parent compds. neamine (1), ribostamycin (2), kanamycin-B (3) and kanamycin-A (4) were evaluated for rRNA binding and MIC values against E. coli (DH5α). The simultaneous presence of ribose and glucose at positions 5 and 6 of the 2-DOS ring led to a significant increase in both both Kd (dissocn. const. of ligand/RNA complex) and MIC; replacement of glucose by xylose, however, produces dramatic improvement in both Kd and MIC.
101
Herzog, I. M., Louzoun Zada, S., and Fridman, M. (2016) Effects of 5-O-Ribosylation of Aminoglycosides on Antimicrobial Activity and Selective Perturbation of Bacterial Translation. J. Med. Chem. 59, 8008– 8018, DOI: 10.1021/acs.jmedchem.6b00793
Google Scholar
101
Effects of 5-O-Ribosylation of Aminoglycosides on Antimicrobial Activity and Selective Perturbation of Bacterial Translation
Herzog, Ido M.; Louzoun Zada, Sivan; Fridman, Micha
Journal of Medicinal Chemistry (2016), 59 (17), 8008-8018CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
We studied six pairs of aminoglycosides and their corresponding ribosylated derivs. synthesized by attaching a β-O-linked ribofuranose to the 5-OH of the deoxystreptamine ring of the parent pseudooligosaccharide antibiotic. Ribosylation of the 4,6-disubstituted 2-deoxystreptamine aminoglycoside kanamycin B led to improved selectivity for inhibition of prokaryotic relative to eukaryotic in vitro translation. For the pseudo-disaccharide aminoglycoside scaffolds neamine and nebramine, ribosylated derivs. were both more potent antimicrobials and more selective to inhibition of prokaryotic translation. Based on the results of this study we suggest that modification of the 5-OH position of the streptamine ring of other natural or semi-synthetic pseudo-disaccharide aminoglycoside scaffolds contg. an equatorial amine at the 2' sugar position with a β-O-linked ribofuranoside is a promising avenue for the development of novel aminoglycoside antibiotics with improved efficacy and reduced toxicity.
102
Asako, T., Yoshioka, K., Mabuchi, H., and Hiraga, K. (1978) Chemical Transformation of 3′-Chloro-3′-deoxyaminoglycosides into New Cyclic Pseudo-trisaccharides. Heterocycles 11, 197– 2002, DOI: 10.3987/S(N)-1978-01-0197
Google Scholar
102
Chemical transformation of 3'-chloro-3'-deoxyaminoglycosides into new cyclic pseudo-trisaccharides
Asako, Tsunehiko; Yoshioka, Kouichi; Mabuchi, Hiroshi; Hiraga, Kentaro
Heterocycles (1978), 11 (), 197-202CODEN: HTCYAM; ISSN:0385-5414.
Treatment of the aminoglycosides [I; R = H, H2NCH2CH2CH(OH)CO; R1 = Cl, R2 = H] with a base gave cyclic pseudotrisaccharides II as the major products and I (R as before, R1 = H, R2 = OH) as the minor products.
103
Morgenthaler, M., Schweizer, E., Hoffmann-Roder, A., Benini, F., Martin, R. E., Jaeschke, G., Wagner, B., Fischer, H., Bendels, S., Zimmerli, D., Schneider, J., Diederich, F., Kansy, M., and Muller, K. (2007) Predicting and Tuning Physicochemical Properties in Lead Optimization: Amine Basicities. ChemMedChem 2, 1100– 1115, DOI: 10.1002/cmdc.200700059
Google Scholar
103
Predicting and tuning physicochemical properties in lead optimization: amine basicities
Morgenthaler, Martin; Schweizer, Eliane; Hoffmann-Roder, Anja; Benini, Fausta; Martin, Rainer E.; Jaeschke, Georg; Wagner, Bjorn; Fischer, Holger; Bendels, Stefanie; Zimmerli, Daniel; Schneider, Josef; Diederich, Francois; Kansy, Manfred; Muller, Klaus
ChemMedChem (2007), 2 (8), 1100-1115CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. This review describes simple and useful concepts for predicting and tuning the pKa values of basic amine centers, a crucial step in the optimization of phys. and ADME properties of many lead structures in drug-discovery research. The article starts with a case study of tricyclic thrombin inhibitors featuring a tertiary amine center with pKa values that can be tuned over a wide range, from the usual value of around 10 to below 2 by (remote) neighboring functionalities commonly encountered in medicinal chem. Next, the changes in pKa of acyclic and cyclic amines upon substitution by fluorine, oxygen, nitrogen, and sulfur functionalities, as well as carbonyl and carboxyl derivs. are systematically analyzed, leading to the derivation of simple rules for pKa prediction. Electronic and stereoelectronic effects in cyclic amines are discussed, and the emerging computational methods for pKa predictions are briefly surveyed. The rules for tuning amine basicities should not only be of interest in drug-discovery research, but also to the development of new crop-protection agents, new amine ligands for organometallic complexes, and in particular, to the growing field of amine-based organocatalysis.
104
Barbieri, C. M., Kaul, M., Bozza-Hingos, M., Zhao, F., Tor, Y., Hermann, T., and Pilch, D. S. (2007) Defining the Molecular Forces That Determine the Impact of Neomycin on Bacterial Protein Synthesis: Importance of the 2-Amino Functionality. Antimicrob. Agents Chemother. 51, 1760– 1769, DOI: 10.1128/AAC.01267-06
Google Scholar
104
Defining the molecular forces that determine the impact of neomycin on bacterial protein synthesis: importance of the 2'-amino functionality
Barbieri, Christopher M.; Kaul, Malvika; Bozza-Hingos, Melanie; Zhao, Fang; Tor, Yitzhak; Hermann, Thomas; Pilch, Daniel S.
Antimicrobial Agents and Chemotherapy (2007), 51 (5), 1760-1769CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
2-Deoxystreptamine (2-DOS) aminoglycosides exert their antibiotic actions by binding to the A site of the 16S rRNA and interfering with bacterial protein synthesis. However, the mol. forces that govern the antitranslational activities of aminoglycosides are poorly understood. Here, we describe studies aimed at elucidating these mol. forces. In this connection, we compare the bactericidal, antitranslational, and rRNA binding properties of the 4,5-disubstituted 2-DOS aminoglycoside neomycin (Neo) and a conformationally restricted analog of Neo (CR-Neo) in which the 2'-nitrogen atom is covalently conjugated to the 5''-carbon atom. The bactericidal potency of Neo exceeds that of CR-Neo, with this enhanced antibacterial activity reflecting a correspondingly enhanced antitranslational potency. Time-resolved fluorescence anisotropy studies suggest that the enhanced antitranslational potency of Neo relative to that of CR-Neo is due to a greater extent of drug-induced redn. in the mobilities of the nucleotides at positions 1492 and 1493 of the rRNA A site. Buffer- and salt-dependent binding studies, coupled with high-resoln. structural information, point to electrostatic contacts between the 2'-amino functionality of Neo and the host rRNA as being an important modulator of 1492 and 1493 base mobilities and therefore antitranslational activities.

Cited By

Click to copy section linkSection link copied!

Explore this article's citation statements on scite.ai

This article is cited by 28 publications.

Christian Hobson, Andrew N. Chan, Gerard D. Wright. The Antibiotic Resistome: A Guide for the Discovery of Natural Products as Antimicrobial Agents. Chemical Reviews 2021, 121 (6) , 3464-3494. https://doi.org/10.1021/acs.chemrev.0c01214
Amr Sonousi, Andrea Vasella, David Crich. Synthesis of a Pseudodisaccharide Suitable for Synthesis of Ring I Modified 4,5-2-Deoxystreptamine Type Aminoglycoside Antibiotics. The Journal of Organic Chemistry 2020, 85 (11) , 7583-7587. https://doi.org/10.1021/acs.joc.0c00743
Parasuraman Rajasekaran, David Crich. Synthesis of Gentamicin Minor Components: Gentamicin B1 and Gentamicin X2. Organic Letters 2020, 22 (10) , 3850-3854. https://doi.org/10.1021/acs.orglett.0c01107
Mahnaz Sabeti Azad, Maho Okuda, Mélina Cyrenne, Mickael Bourge, Marie-Pierre Heck, Satoko Yoshizawa, Dominique Fourmy. Fluorescent Aminoglycoside Antibiotics and Methods for Accurately Monitoring Uptake by Bacteria. ACS Infectious Diseases 2020, 6 (5) , 1008-1017. https://doi.org/10.1021/acsinfecdis.9b00421
Abd Al-Aziz A. Abu-Saleh, Sweta Sharma, Arpita Yadav, Raymond A. Poirier. Role of Asp190 in the Phosphorylation of the Antibiotic Kanamycin Catalyzed by the Aminoglycoside Phosphotransferase Enzyme: A Combined QM:QM and MD Study. The Journal of Physical Chemistry B 2020, 124 (17) , 3494-3504. https://doi.org/10.1021/acs.jpcb.0c01604
Erik C. Böttger, David Crich. Aminoglycosides: Time for the Resurrection of a Neglected Class of Antibacterials?. ACS Infectious Diseases 2020, 6 (2) , 168-172. https://doi.org/10.1021/acsinfecdis.9b00441
Jonathan C. K. Quirke, Parasuraman Rajasekaran, Vikram A. Sarpe, Amr Sonousi, Ivan Osinnii, Marina Gysin, Klara Haldimann, Qiao-Jun Fang, Dimitri Shcherbakov, Sven N. Hobbie, Su-Hua Sha, Jochen Schacht, Andrea Vasella, Erik C. Böttger, David Crich. Apralogs: Apramycin 5-O-Glycosides and Ethers with Improved Antibacterial Activity and Ribosomal Selectivity and Reduced Susceptibility to the Aminoacyltransferase (3)-IV Resistance Determinant. Journal of the American Chemical Society 2020, 142 (1) , 530-544. https://doi.org/10.1021/jacs.9b11601
Shiqing Luo, Xiaojie Sun, Lifang Zhang, Yanming Miao, Guiqin Yan. Mn-doped ZnS quantum dots@dendritic mesoporous silica phosphorescent nanocomposites for antimicrobial susceptibility testing. Sensors and Actuators B: Chemical 2025, 435 , 137664. https://doi.org/10.1016/j.snb.2025.137664
Michel Plattner, Maurizio Catelani, Sarah-Lisa Gmür, Maximilian Hartmann, Fatmanur Kiliç, Klara Haldimann, David Crich, Sven N. Hobbie. Phenotypic Differentiation Within the aac(6′) Aminoglycoside Resistance Gene Family Suggests a Novel Subtype IV of Contemporary Clinical Relevance. Antibiotics 2024, 13 (12) , 1196. https://doi.org/10.3390/antibiotics13121196
Siran Zhao, Tianji Zhang, Ying Kan, Hongmei Li, Jin-ping Li. Overview of the current procedures in synthesis of heparin saccharides. Carbohydrate Polymers 2024, 339 , 122220. https://doi.org/10.1016/j.carbpol.2024.122220
Marharyta Hancharova, Kinga Halicka-Stępień, Aleksandra Dupla, Anna Lesiak, Jadwiga Sołoducho, Joanna Cabaj. Antimicrobial activity of metal-based nanoparticles: a mini-review. BioMetals 2024, 37 (4) , 773-801. https://doi.org/10.1007/s10534-023-00573-y
Nittert Marinus, Niels R. M. Reintjens, Klara Haldimann, Marc L. M. C. Mouthaan, Sven N. Hobbie, Martin D. Witte, Adriaan J. Minnaard. Site‐Selective Palladium‐catalyzed Oxidation of Unprotected Aminoglycosides and Sugar Phosphates. Chemistry – A European Journal 2024, 30 (19) https://doi.org/10.1002/chem.202400017
Tushar Tiwari, Divya Pratap Nain, Nisha Gaur, Eti Sharma. Countering Aminoglycoside Modifying Enzymes. 2024, 119-147. https://doi.org/10.4018/979-8-3693-1540-8.ch005
Emily Bordeleau, Peter J. Stogios, Elena Evdokimova, Kalinka Koteva, Alexei Savchenko, Gerard D. Wright. Mechanistic plasticity in ApmA enables aminoglycoside promiscuity for resistance. Nature Chemical Biology 2024, 20 (2) , 234-242. https://doi.org/10.1038/s41589-023-01483-3
Hadi Jabbari. Synthesis of New Glycosylamine Derivatives based on Carbohydrates. Current Bioactive Compounds 2024, 20 (2) https://doi.org/10.2174/1573407219666230810094657
Ayan Mukherjee, Danyel Ramirez, Rajat Arora, Gilbert Arthur, Frank Schweizer. Amphiphilic tribasic galactosamines potentiate rifampicin in Gram-negative bacteria at low Mg++/Ca++concentrations. Bioorganic & Medicinal Chemistry Letters 2024, 97 , 129371. https://doi.org/10.1016/j.bmcl.2023.129371
Mnaza Noreen, Muhammad Bilal, Muhammad Usman Qamar, Nasir Rasool, Abid Mahmood, Sobia Umar Din, Tawaf Ali Shah, Yousef Bin Jardan, Mohammed Bourhia, Lahcen Ouahmane. Facile Synthesis of 5-Bromo-N-Alkylthiophene-2-Sulfonamides and Its Activities Against Clinically Isolated New Delhi Metallo-β-Lactamase Producing Klebsiella pneumoniae ST147. Infection and Drug Resistance 2024, Volume 17 , 2943-2955. https://doi.org/10.2147/IDR.S455979
Conor J. Crawford, Peter H. Seeberger. Advances in glycoside and oligosaccharide synthesis. Chemical Society Reviews 2023, 52 (22) , 7773-7801. https://doi.org/10.1039/D3CS00321C
Xiaohan Zhai, Guoyu Wu, Xufeng Tao, Shilei Yang, Linlin Lv, Yanna Zhu, Deshi Dong, Hong Xiang. Success stories of natural product-derived compounds from plants as multidrug resistance modulators in microorganisms. RSC Advances 2023, 13 (12) , 7798-7817. https://doi.org/10.1039/D3RA00184A
Michael G. Pirrone, Chennaiah Ande, Klara Haldimann, Sven N. Hobbie, Andrea Vasella, Erik C. Böttger, David Crich. Importance of Co‐operative Hydrogen Bonding in the Apramycin‐Ribosomal Decoding A‐Site Interaction. ChemMedChem 2023, 18 (1) https://doi.org/10.1002/cmdc.202200486
Ribai Yan, Xiaonan Li, Yuheng Liu, Xinshan Ye. Design, Synthesis, and Bioassay of 2′-Modified Kanamycin A. Molecules 2022, 27 (21) , 7482. https://doi.org/10.3390/molecules27217482
J. Obszynski, H. Loidon, A. Blanc, J.-M. Weibel, P. Pale. Targeted modifications of neomycin and paromomycin: Towards resistance-free antibiotics?. Bioorganic Chemistry 2022, 126 , 105824. https://doi.org/10.1016/j.bioorg.2022.105824
Yan Li, Ting-Biao Wan, Bin Guo, Xiao-Wen Qi, Chifan Zhu, Mei-Hua Shen, Hua-Dong Xu. Quaternization of azido-N-heteroarenes with Meerwein reagent: A straightforward synthesis of 2-azido(benzo)imidazolium and related azido-N-heteroarenium tetrafluoroborates. Tetrahedron Letters 2022, 106 , 154063. https://doi.org/10.1016/j.tetlet.2022.154063
Jonathan C. K. Quirke, Girish C. Sati, Amr Sonousi, Marina Gysin, Klara Haldimann, Erik C. Böttger, Andrea Vasella, Sven N. Hobbie, David Crich. Structure‐Activity Relationships for 5′′ Modifications of 4,5‐Aminoglycoside Antibiotics. ChemMedChem 2022, 17 (13) https://doi.org/10.1002/cmdc.202200120
Tolou Golkar, Angelia V. Bassenden, Krishnagopal Maiti, Dev P. Arya, T. Martin Schmeing, Albert M. Berghuis. Structural basis for plazomicin antibiotic action and resistance. Communications Biology 2021, 4 (1) https://doi.org/10.1038/s42003-021-02261-4
Laiying Zhang, Jun He, Lang Bai, Shihua Ruan, Tao Yang, Youfu Luo. Ribosome‐targeting antibacterial agents: Advances, challenges, and opportunities. Medicinal Research Reviews 2021, 41 (4) , 1855-1889. https://doi.org/10.1002/med.21780
Zoe L Watson, Fred R Ward, Raphaël Méheust, Omer Ad, Alanna Schepartz, Jillian F Banfield, Jamie HD Cate. Structure of the bacterial ribosome at 2 Å resolution. eLife 2020, 9 https://doi.org/10.7554/eLife.60482
Ji Zhang, Liubov Yakovlieva, Bart J. de Haan, Paul de Vos, Adriaan J. Minnaard, Martin D. Witte, Marthe T. C. Walvoort. Selective Modification of Streptozotocin at the C3 Position to Improve Its Bioactivity as Antibiotic and Reduce Its Cytotoxicity towards Insulin-Producing β Cells. Antibiotics 2020, 9 (4) , 182. https://doi.org/10.3390/antibiotics9040182

Download PDF

Get e-Alerts

ACS Infectious Diseases

Cite this: ACS Infect. Dis. 2019, 5, 10, 1718–1730

Click to copy citationCitation copied!

https://doi.org/10.1021/acsinfecdis.9b00128

Published August 22, 2019

Request reuse permissions

Article Views

Altmetric

Citations

Learn about these metrics

Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.

Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.

The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.

Abstract
High Resolution Image
Download MS PowerPoint Slide
Scheme 1
Scheme 1. Synthesis of 2′-N-Alkyl Derivatives of Paromomycin and Neomycin
High Resolution Image
Download MS PowerPoint Slide
Scheme 2
Scheme 2. Synthesis of 2′-Desamino-2′-hydroxy Paromomycin and Neomycin Derivatives
High Resolution Image
Download MS PowerPoint Slide
Scheme 3
Scheme 3. Synthesis of 2′-Desamino Neomycin
High Resolution Image
Download MS PowerPoint Slide
Scheme 4
Scheme 4. Synthesis of Neomycin 2′-Amides
High Resolution Image
Download MS PowerPoint Slide
Scheme 5
Scheme 5. Synthesis of Ribostamycin Derivatives 41, 42, and 46
High Resolution Image
Download MS PowerPoint Slide
Figure 1
Figure 1. Some natural and semisynthetic aminoglycoside antibiotics.
High Resolution Image
Download MS PowerPoint Slide
Scheme 6
Scheme 6. Synthesis of Ribostamycin Derivatives 59 and 60
High Resolution Image
Download MS PowerPoint Slide
Figure 2
Figure 2. Decoding A sites of prokaryotic and eukaryotic ribosomes. The bacterial AGA binding pocket is boxed. The bacterial numbering scheme is illustrated for the AGA binding pocket. Changes from the bacterial ribosome binding pocket are colored green. The A1555G mutant conferring hypersusceptibility to AGA ototoxicity is colored red.
High Resolution Image
Download MS PowerPoint Slide
Figure 3
Figure 3. Schematic of the crystallographically determined interactions of neomycin 3 (X = NH₂⁺) and paromomycin 2 (X = O) with the AGA binding pocket. Ribostamycin 6 (X = NH₂⁺) binds identically but lacks ring IV.
High Resolution Image
Download MS PowerPoint Slide
References
This article references 104 other publications.
1. 1
  Chang, H.-H., Cohen, T., Grad, Y. H., Hanage, W. P., O’Brien, T. F., and Lipsitch, M. (2015) Origin and Proliferation of Multiple-Drug Resistance in Bacterial Pathogens. Microbiol. Mol. Biol. Rev. 79, 101– 116, DOI: 10.1128/MMBR.00039-14
  1
  Origin and proliferation of multiple-drug resistance in bacterial pathogens
  Chang, Hsiao-Han; Cohen, Ted; Grad, Yonatan H.; Hanage, William P.; O'Brien, Thomas F.; Lipsitch, Marc
  Microbiology and Molecular Biology Reviews (2015), 79 (1), 101-116CODEN: MMBRF7; ISSN:1098-5557. (American Society for Microbiology)
  Many studies report the high prevalence of multiply drug-resistant (MDR) strains. Because MDR infections are often significantly harder and more expensive to treat, they represent a growing public health threat. However, for different pathogens, different underlying mechanisms are traditionally used to explain these observations, and it is unclear whether each bacterial taxon has its own mechanism(s) for multidrug resistance or whether there are common mechanisms between distantly related pathogens. In this review, we provide a systematic overview of the causes of the excess of MDR infections and define testable predictions made by each hypothetical mechanism, including exptl., epidemiol., population genomic, and other tests of these hypotheses. Better understanding the cause(s) of the excess of MDR is the first step to rational design of more effective interventions to prevent the origin and/or proliferation of MDR.
2. 2
  Fisher, J. F. and Mobashery, S. (2016) Endless Resistance. Endless Antibiotics?. MedChemComm 7, 37– 49, DOI: 10.1039/C5MD00394F
  2
  Endless resistance. Endless antibiotics?
  Fisher, Jed F.; Mobashery, Shahriar
  MedChemComm (2016), 7 (1), 37-49CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
  The practice of medicine was profoundly transformed by the introduction of the antibiotics (compds. isolated from Nature) and the antibacterials (compds. prepd. by synthesis) for the control of bacterial infection. As a result of the extraordinary success of these compds. over decades of time, a timeless biol. activity for these compds. has been presumed. This presumption is no longer. The inexorable acquisition of resistance mechanisms by bacteria is retransforming medical practice. Credible answers to this dilemma are far better recognized than they are being implemented. In this perspective we examine (and in key respects, reiterate) the chem. and biol. strategies being used to address the challenge of bacterial resistance.
3. 3
  Pendleton, J. N., Gorman, S. P., and Gilmore, B. F. (2013) Clinical Relevance of ESKAPE Pathogens. Expert Rev. Anti-Infect. Ther. 11, 297– 308, DOI: 10.1586/eri.13.12
  3
  Clinical relevance of the ESKAPE pathogens
  Pendleton, Jack N.; Gorman, Sean P.; Gilmore, Brendan F.
  Expert Review of Anti-Infective Therapy (2013), 11 (3), 297-308CODEN: ERATCK; ISSN:1478-7210. (Expert Reviews Ltd.)
  A review. In recent years, the Infectious Diseases Society of America has highlighted a faction of antibiotic-resistant bacteria (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) - acronymically dubbed the ESKAPE pathogens' - capable of escaping' the biocidal action of antibiotics and mutually representing new paradigms in pathogenesis, transmission and resistance. This review aims to consolidate clin. relevant background information on the ESKAPE pathogens and provide a contemporary summary of bacterial resistance, alongside pertinent microbiol. considerations necessary to face the mounting threat of antimicrobial resistance.
4. 4
  O'Connell, K. M. G., Hodgkinson, J. T., Sore, H. F., Welch, M., Salmond, G. P. C., and Spring, D. R. (2013) Combating Multidrug-Resistant Bacteria: Current Strategies for the Discovery of Novel Antibacterials. Angew. Chem., Int. Ed. 52, 10706– 10733, DOI: 10.1002/anie.201209979
  4
  Combating Multidrug-Resistant Bacteria: Current Strategies for the Discovery of Novel Antibacterials
  O'Connell, Kieron M. G.; Hodgkinson, James T.; Sore, Hannah F.; Welch, Martin; Salmond, George P. C.; Spring, David R.
  Angewandte Chemie, International Edition (2013), 52 (41), 10706-10733CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. The introduction of effective antibacterial therapies for infectious diseases in the mid-20th century completely revolutionized clin. practices and helped to facilitate the development of modern medicine. Many potentially life-threatening conditions became easily curable, greatly reducing the incidence of death or disability resulting from bacterial infections. This overwhelming historical success makes it very difficult to imagine life without effective antibacterials; however, the inexorable rise of antibiotic resistance has made this a very real and disturbing possibility for some infections. The ruthless selection for resistant bacteria, coupled with insufficient investment in antibacterial research, has led to a steady decline in the efficacy of existing therapies and a paucity of novel structural classes with which to replace them, or complement their use. This situation has resulted in a very pressing need for the discovery of novel antibiotics and treatment strategies, the development of which is likely to be a key challenge to 21st century medicinal chem.
5. 5
  Wright, G. D. (2015) Solving the Antibiotic Crisis. ACS Infect. Dis. 1, 80– 84, DOI: 10.1021/id500052s
  5
  Solving the Antibiotic Crisis
  Wright, Gerard D.
  ACS Infectious Diseases (2015), 1 (2), 80-84CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)
  A review. Antibiotics are essential for both treating and preventing infectious diseases. Paradoxically, despite their importance as pillars of modern medicine, we are in danger of losing antibiotics because of the evolution and dissemination of resistance mechanisms throughout all pathogenic microbes. This fact, coupled with an inability to bring new drugs to market at a pace that matches resistance, has resulted in a crisis of global proportion. Solving this crisis requires the actions of many stakeholders, but chemists, chem. biologists, and microbiologists must drive the scientific innovation that is required to maintain our antibiotic arsenal. This innovation requires (1) a deep understanding of the evolution and reservoirs of resistance; (2) full knowledge of the mol. mechanisms of antibiotic action and resistance; (3) the discovery of chem. and genetic probes of antibiotic action and resistance; (4) the integration of systems biol. into antibiotic discovery; and (5) the discovery of new antimicrobial chem. matter. Addressing these pressing scientific gaps will ensure that we can meet the antibiotic crisis with creativity and purpose.
6. 6
  Wright, P. M., Seiple, I. B., and Myers, A. G. (2014) The Evolving Role of Chemical Synthesis in Antibacterial Drug Discovery. Angew. Chem., Int. Ed. 53, 8840– 8863, DOI: 10.1002/anie.201310843
  6
  The Evolving Role of Chemical Synthesis in Antibacterial Drug Discovery
  Wright, Peter M.; Seiple, Ian B.; Myers, Andrew G.
  Angewandte Chemie, International Edition (2014), 53 (34), 8840-8869CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. The discovery and implementation of antibiotics in the early twentieth century transformed human health and wellbeing. Chem. synthesis enabled the development of the first antibacterial substances, organoarsenicals and sulfa drugs, but these were soon outshone by a host of more powerful and vastly more complex antibiotics from nature: penicillin, streptomycin, tetracycline, and erythromycin, among others. These primary defences are now significantly less effective as an unavoidable consequence of rapid evolution of resistance within pathogenic bacteria, made worse by widespread misuse of antibiotics. For decades medicinal chemists replenished the arsenal of antibiotics by semisynthetic and to a lesser degree fully synthetic routes, but economic factors have led to a subsidence of this effort, which places society on the precipice of a disaster. We believe that the strategic application of modern chem. synthesis to antibacterial drug discovery must play a crit. role if a crisis of global proportions is to be averted.
7. 7
  Umezawa, S. (1974) Structures and Syntheses of Aminoglycoside Antibiotics. Adv. Carbohydr. Chem. Biochem. 30, 111– 182, DOI: 10.1016/S0065-2318(08)60264-4
  7
  Structures and syntheses of aminoglycoside antibiotics
  Umezawa, Sumio
  Advances in Carbohydrate Chemistry and Biochemistry (1974), 30 (), 111-82CODEN: ACBYAP; ISSN:0065-2318.
  A review with 254 refs. on structures, synthesis and chem. modifications of aminoglycoside antibiotics.
8. 8
  Haddad, J., Kotra, L. P., and Mobashery, S. (2001) in Glycochemsitry: Principles, Synthesis, and Applications (Wang, P. G., and Bertozzi, C. R., Eds.) pp 307– 351, Dekker, New York.
  There is no corresponding record for this reference.
9. 9
  Vakulenko, S. B. and Mobashery, S. (2003) Versatility of Aminoglycosides and Prospects for Their Future. Clin. Microbiol. Rev. 16, 430– 450, DOI: 10.1128/CMR.16.3.430-450.2003
  9
  Versatility of aminoglycosides and prospects for their future
  Vakulenko, Sergei B.; Mobashery, Shahriar
  Clinical Microbiology Reviews (2003), 16 (3), 430-450CODEN: CMIREX; ISSN:0893-8512. (American Society for Microbiology)
  A review. Aminoglycoside antibiotics have had a major impact on our ability to treat bacterial infections for the past half century. Whereas the interest in these versatile antibiotics continues to be high, their clin. utility has been compromised by widespread instances of resistance. The multitude of mechanisms of resistance is disconcerting but also illuminates how Nature can manifest resistance when bacteria are confronted by antibiotics. This article reviews the most recent knowledge about the mechanisms of aminoglycoside action and the mechanisms of resistance to these antibiotics.
10. 10
  (2007) Aminoglycoside Antibiotics: From Chemical Biology to Drug Discovery (Arya, D. P., Ed.) Wiley, Hoboken, NJ.
  There is no corresponding record for this reference.
11. 11
  Jackson, J., Chen, C., and Buising, K. (2013) Aminoglycosides: How Should We Use Them in the 21st Century?. Curr. Opin. Infect. Dis. 26, 516– 525, DOI: 10.1097/QCO.0000000000000012
  11
  Aminoglycosides: how should we use them in the 21st century?
  Jackson, Justin; Chen, Caroline; Buising, Kirsty
  Current Opinion in Infectious Diseases (2013), 26 (6), 516-525CODEN: COIDE5; ISSN:0951-7375. (Lippincott Williams & Wilkins)
  Purpose of review: Aminoglycoside antibiotics (AGAs) have proved an invaluable part of our antimicrobial armamentarium since their introduction into practice over 60 years ago. This review summarizes recent developments, defining their role in the context of the current global epidemic of antibiotic resistance, raising awareness of their toxicity profile, and highlighting current data on their utility as synergistic agents. Recent findings: Clinicians are facing an unprecedented threat from antibiotic resistance, resulting in an increased reliance on the addn. of an AGA to provide adequate empirical cover in cases of severe sepsis. Concurrently, an increased awareness of the potential for severe disability, particularly from vestibular toxicity, has restrained directed therapy of AGAs to situations in which there are no appropriate alternatives. Their role as synergistic agents in the treatment of enterococcal endocarditis is currently under reevaluation, and new data have emerged on combination therapy for Pseudomonas aeruginosa bacteremia. AGAs are themselves coming under increasing threat from resistance, predominately from aminoglycoside modifying enzymes (mediating selective resistance) and 16S rRNA methyltransferases (conferring class-wide resistance). New agents and the development of alternate ways to circumvent resistance are likely to have important roles in future clin. care. Summary: Aminoglycosides retain an invaluable but well defined role, and will remain important agents into the foreseeable future.
12. 12
  Vicens, Q. and Westhof, E. (2003) RNA as a Drug Target: The Case of Aminoglycosides. ChemBioChem 4, 1018– 1023, DOI: 10.1002/cbic.200300684
  12
  RNA as a drug target: The case of aminoglycosides
  Vicens, Quentin; Westhof, Eric
  ChemBioChem (2003), 4 (10), 1018-1023CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review discusses the interactions between aminoglycosides and the 16S rRNA, as well as the challenges small mols. must face to target RNA. It describes the mol. recognition between rRNA and aminoglycosides as well as the mechanism of action of aminoglycoside antibiotics. It discusses how strategies aimed at overcoming resistance due to RNA modifications or mutations need to cope with toxicity. The advantages of targeting RNA mol. switches, whose occurrence is now revealed in various RNA mols., are also considered.
13. 13
  Kondo, J., and Westhof, E. (2014) in Antibioitcs: Targets, Mechanisms and Resistance (Gualerzi, C. O., Brandi, L., Fabbretti, A., and Pon, C. L., Eds.) pp 453– 470, Wiley-VCH, Weinheim.
  There is no corresponding record for this reference.
14. 14
  Haddad, J., Liu, M.-Z., and Mobashery, S. (2001) in Glycochemistry: Principles, Synthesis, and Applications (Wang, P. G., and Bertozzi, C. R., Eds.) pp 353– 424, Dekker, New York.
  There is no corresponding record for this reference.
15. 15
  Wang, J., and Chang, C.-W. T. (2007) in Aminoglycoside Antibiotics (Arya, D. P., Ed.) pp 141– 180, Wiley, Hoboken, NJ.
  There is no corresponding record for this reference.
16. 16
  Berkov-Zrihen, Y., and Fridman, M. (2014) in Modern Synthetic Methods in Carbohydrate Chemistry; From Monosaccharides to Complex Glycoconjugates (Werz, D. B., and Vidal, S., Eds.) pp 161– 190, Wiley, Weinheim.
  There is no corresponding record for this reference.
17. 17
  Price, K. E., Godfrey, J. C., and Kawaguchi, H. (1974) Effect of Structural Modifications on the Biological Properties of Aminoglycoside Antibiotics Containing 2-Deoxystreptamine. Adv. Appl. Microbiol. 18, 191– 307, DOI: 10.1016/S0065-2164(08)70572-0
  17
  Effect of structural modifications on the biological properties of aminoglycoside antibiotics containing 2-deoxystreptamine
  Price K E; Godfrey J C
  Advances in applied microbiology (1974), 18 (0), 191-307 ISSN:0065-2164.
  There is no expanded citation for this reference.
18. 18
  Becker, B. and Cooper, M. A. (2013) Aminoglycoside Antibiotics in the 21st Century. ACS Chem. Biol. 8, 105– 115, DOI: 10.1021/cb3005116
  18
  Aminoglycoside Antibiotics in the 21st Century
  Becker, Bernd; Cooper, Matthew A.
  ACS Chemical Biology (2013), 8 (1), 105-115CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
  A review. Aminoglycoside antibiotics were among the first antibiotics discovered and used clin. Although they have never completely fallen out of favor, their importance has waned due to the emergence of other broad-spectrum antibiotics with fewer side effects. Today, with the dramatically increasing rate of infections caused by multidrug-resistant bacteria, focus has returned to aminoglycoside antibiotics as one of the few remaining treatment options, particularly for Gram-neg. pathogens. Although the mechanisms of resistance are reasonably well understood, our knowledge about the mode of action of aminoglycosides is still far from comprehensive. In the face of emerging bacterial infections that are virtually untreatable, it is time to have a fresh look at this old class to reinvigorate the struggle against multidrug-resistant pathogens.
19. 19
  Yang, L. and Ye, X. S. (2010) Development of Aminoglycoside Antibiotics Effective Against Resistant Bacterial Strains. Curr. Top. Med. Chem. 10, 1898– 1926, DOI: 10.2174/156802610793176684
  19
  Development of aminoglycoside antibiotics effective against resistant bacterial strains
  Yang, Lin; Ye, Xin-Shan
  Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2010), 10 (18), 1898-1926CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)
  A review. Aminoglycosides are important broad-spectrum antibiotics used in the therapy of many microbial infections. As the bacterial resistance to antibiotic therapy is appearing as an increasingly significant threat to public health, the development of aminoglycoside antibiotics with extended antibacterial spectrum and potency, devoid of nephro- and ototoxicity, and evading the resistance process returns to the focus of researchers. In this review, various developments brought to the aminoglycoside family of antibiotics effective against resistant bacteria have been described, focused on chem. modifications, drug-modifying enzyme inhibitors, and conformationally constrained analogs, as well as related antibacterial compds., with the hope to provide information useful in rational design of novel antibiotics addressing bacterial resistance, and paving the way for new perspectives in antimicrobial therapy.
20. 20
  Armstrong, E. S., Kostrub, C. F., Cass, R. T., Moser, H. E., Serio, A. W., and Miller, G. H. (2012) in Antibiotic Discovery and Development (Dougherty, T. J., and Pucci, M. J., Eds.) pp 229– 269, Springer Science+Business Media, New York.
  There is no corresponding record for this reference.
21. 21
  Chandrika, N. T. and Garneau-Tsodikova, S. (2016) A Review of Patents (2011–2015) Towards Combating Resistance to and Toxicity of Aminoglycosides. MedChemComm 7, 50– 68, DOI: 10.1039/C5MD00453E
  21
  A review of patents (2011-2015) towards combating resistance to and toxicity of aminoglycosides
  Chandrika, Nishad Thamban; Garneau-Tsodikova, Sylvie
  MedChemComm (2016), 7 (1), 50-68CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
  Since the discovery of the first aminoglycoside (AG), streptomycin, in 1943, these broad-spectrum antibiotics have been extensively used for the treatment of Gram-neg. and Gram-pos. bacterial infections. The inherent toxicity (ototoxicity and nephrotoxicity) assocd. with their long-term use as well as the emergence of resistant bacterial strains have limited their usage. Structural modifications of AGs by AG-modifying enzymes, reduced target affinity caused by ribosomal modification, and decrease in their cellular concn. by efflux pumps have resulted in resistance towards AGs. However, the last decade has seen a renewed interest among the scientific community for AGs as exemplified by the recent influx of scientific articles and patents on their therapeutic use. In this review, we use a non-conventional approach to put forth this renaissance on AG development/application by summarizing all patents filed on AGs from 2011-2015 and highlighting some related publications on the most recent work done on AGs to overcome resistance and improving their therapeutic use while reducing ototoxicity and nephrotoxicity. We also present work towards developing amphiphilic AGs for use as fungicides as well as that towards repurposing existing AGs for potential newer applications.
22. 22
  Thamban Chandrika, N. and Garneau-Tsodikova, S. (2018) Comprehensive Review of Chemical Strategies for the Preparation of New Aminoglycosides and their Biological Activities. Chem. Soc. Rev. 47, 1189– 1249, DOI: 10.1039/C7CS00407A
  22
  Comprehensive review of chemical strategies for the preparation of new aminoglycosides and their biological activities
  Thamban Chandrika, Nishad; Garneau-Tsodikova, Sylvie
  Chemical Society Reviews (2018), 47 (4), 1189-1249CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
  A systematic anal. of all synthetic and chemoenzymic methodologies for the prepn. of aminoglycosides for a variety of applications (therapeutic and agricultural) reported in the scientific literature up to 2017 is presented. This comprehensive anal. of derivatization/generation of novel aminoglycosides and their conjugates is divided based on the types of modifications used to make the new derivs. Both the chem. strategies utilized and the biol. results obsd. are covered. Structure-activity relationships based on different synthetic modifications along with their implications for activity and ability to avoid resistance against different microorganisms are also presented.
23. 23
  Zárate, S. G., De la Cruz Claure, M. L., Benito-Arenas, R., Revuelta, R., Santana, A. G., and Bastida, A. (2018) Overcoming Aminoglycoside Enzymatic Resistance: Design of Novel Antibiotics and Inhibitors. Molecules 23, 284, DOI: 10.3390/molecules23020284
  23
  Overcoming aminoglycoside enzymatic resistance: design of novel antibiotics and inhibitors
  Zarate, Sandra G.; Claure, M. Luisa De la Cruz; Benito-Arenas, Raul; Revuelta, Julia; Santana, Andres G.; Bastida, Agatha
  Molecules (2018), 23 (2), 284/1-284/18CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
  Resistance to aminoglycoside antibiotics has had a profound impact on clin. practice. Despite their powerful bactericidal activity, aminoglycosides were one of the first groups of antibiotics to meet the challenge of resistance. The most prevalent source of clin. relevant resistance against these therapeutics is conferred by the enzymic modification of the antibiotic. Therefore, a deeper knowledge of the aminoglycoside-modifying enzymes and their interactions with the antibiotics and solvent is of paramount importance in order to facilitate the design of more effective and potent inhibitors and/or novel semisynthetic aminoglycosides that are not susceptible to modifying enzymes.
24. 24
  Takahashi, Y. and Igarashi, M. (2018) Destination of Aminoglycoside Antibiotics in the ‘Post-Antibiotic Era’. J. Antibiot. 71, 4– 14, DOI: 10.1038/ja.2017.117
  24
  Destination of aminoglycoside antibiotics in the 'post-antibiotic era'
  Takahashi, Yoshiaki; Igarashi, Masayuki
  Journal of Antibiotics (2018), 71 (1), 4-14CODEN: JANTAJ; ISSN:0021-8820. (Nature Research)
  A review. Aminoglycoside antibiotics (AGAs) were developed at the dawn of the antibiotics era and have significantly aided in the treatment of infectious diseases. Aminoglycosides have become one of the four major types of antibiotics in use today and, fortunately, still have an important role in the clin. treatment of severe bacterial infections. In this review, the current usage, modes of action and side effects of AGAs, along with the most common bacterial resistance mechanisms, are outlined. Finally, the recent development situation and possibility of new AGAs in the 'post-antibiotic era' are considered.
25. 25
  Aggen, J. B., Armstrong, E. S., Goldblum, A. A., Dozzo, P., Linsell, M. S., Gliedt, M. J., Hildebrandt, D. J., Feeney, L. A., Kubo, A., Matias, R. D., Lopez, S., Gomez, M., Wlasichuk, K. B., Diokno, R., Miller, G. H., and Moser, H. E. (2010) Synthesis and Spectrum of the Neoglycoside ACHN-490. Antimicrob. Agents Chemother. 54, 4636– 4642, DOI: 10.1128/AAC.00572-10
  25
  Synthesis and spectrum of the neoglycoside ACHN-490
  Aggen, James B.; Armstrong, Eliana S.; Goldblum, Adam A.; Dozzo, Paola; Linsell, Martin S.; Gliedt, Micah J.; Hildebrandt, Darin J.; Feeney, Lee Ann; Kubo, Aya; Matias, Rowena D.; Lopez, Sara; Gomez, Marcela; Wlasichuk, Kenneth B.; Diokno, Raymond; Miller, George H.; Moser, Heinz E.
  Antimicrobial Agents and Chemotherapy (2010), 54 (11), 4636-4642CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
  ACHN-490 is a neoglycoside, or "next-generation" aminoglycoside (AG), that has been identified as a potentially useful agent to combat drug-resistant bacteria emerging in hospitals and health care facilities around the world. A focused medicinal chem. campaign produced a collection of over 400 sisomicin analogs from which ACHN-490 was selected. The authors tested ACHN-490 against two panels of Gram-neg. and Gram-pos. pathogens, many of which harbored AG resistance mechanisms. Unlike legacy AGs, ACHN-490 was active against strains expressing known AG-modifying enzymes, including the three most common such enzymes found in Enterobacteriaceae. ACHN-490 inhibited the growth of AG-resistant Enterobacteriaceae (MIC90, ≤4 μg/mL), with the exception of Proteus mirabilis and indole-pos. Proteae (MIC90, 8 μg/mL and 16 μg/mL, resp.). ACHN-490 was more active alone in vitro against Pseudomonas aeruginosa and Acinetobacter baumannii isolates with AG-modifying enzymes than against those with altered permeability/efflux. The MIC90 of ACHN-490 against AG-resistant staphylococci was 2 μg/mL. Due to its promising in vitro and in vivo profiles, ACHN-490 has been advanced into clin. development as a new antibacterial agent.
26. 26
  Cox, G., Ejim, L., Stogios, P. J., Koteva, K., Bordeleau, E., Evdokimova, E., Sieron, A. O., Savchenko, A., Serio, A. W., Krause, K. M., and Wright, G. D. (2018) Plazomicin Retains Antibiotic Activity against Most Aminoglycoside Modifying Enzymes. ACS Infect. Dis. 4, 980– 987, DOI: 10.1021/acsinfecdis.8b00001
  26
  Plazomicin Retains Antibiotic Activity against Most Aminoglycoside Modifying Enzymes
  Cox, Georgina; Ejim, Linda; Stogios, Peter J.; Koteva, Kalinka; Bordeleau, Emily; Evdokimova, Elena; Sieron, Arthur O.; Savchenko, Alexei; Serio, Alisa W.; Krause, Kevin M.; Wright, Gerard D.
  ACS Infectious Diseases (2018), 4 (6), 980-987CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)
  Plazomicin is a next-generation, semisynthetic aminoglycoside antibiotic currently under development for the treatment of infections due to multidrug-resistant Enterobacteriaceae. The compd. was designed by chem. modification of the natural product sisomicin to provide protection from common aminoglycoside modifying enzymes that chem. alter these drugs via N-acetylation, O-adenylylation, or O-phosphorylation. In this study, plazomicin was profiled against a panel of isogenic strains of Escherichia coli individually expressing twenty-one aminoglycoside resistance enzymes. Plazomicin retained antibacterial activity against 15 of the 17 modifying enzyme-expressing strains tested. Expression of only two of the modifying enzymes, aac(2')-Ia and aph(2'')-IVa, decreased plazomicin potency. On the other hand, expression of 16S rRNA ribosomal methyltransferases results in a complete lack of plazomicin potency. In vitro enzymic assessment confirmed that AAC(2')-Ia and APH(2'')-IVa (aminoglycoside acetyltransferase, AAC; aminoglycoside phosphotransferase, APH) were able to utilize plazomicin as a substrate. AAC(2')-Ia and APH(2'')-IVa are limited in their distribution to Providencia stuartii and Enterococci, resp. These data demonstrate that plazomicin is not modified by a broad spectrum of common aminoglycoside modifying enzymes including those commonly found in Enterobacteriaceae. However, plazomicin is inactive in the presence of 16S rRNA ribosomal methyltransferases, which should be monitored in future surveillance programs.
27. 27
  Magnet, S. and Blanchard, J. S. (2005) Molecular Insights into Aminoglycoside Action and Resistance. Chem. Rev. 105, 477– 497, DOI: 10.1021/cr0301088
  27
  Molecular Insights into Aminoglycoside Action and Resistance
  Magnet, Sophie; Blanchard, John S.
  Chemical Reviews (Washington, DC, United States) (2005), 105 (2), 477-497CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
  A review. The review discusses the mechanism of action, properties, clin. uses of, and resistance to aminoglycoside antibiotics.
28. 28
  Ramirez, M. S. and Tolmasky, M. E. (2010) Aminoglycoside Modifiying Enzymes. Drug Resist. Updates 13, 151– 171, DOI: 10.1016/j.drup.2010.08.003
  28
  Aminoglycoside modifying enzymes
  Ramirez, Maria S.; Tolmasky, Marcelo E.
  Drug Resistance Updates (2010), 13 (6), 151-171CODEN: DRUPFW; ISSN:1368-7646. (Elsevier Ltd.)
  A review. Aminoglycosides have been an essential component of the armamentarium in the treatment of life-threatening infections. Unfortunately, their efficacy has been reduced by the surge and dissemination of resistance. In some cases the levels of resistance reached the point that rendered them virtually useless. Among many known mechanisms of resistance to aminoglycosides, enzymic modification is the most prevalent in the clin. setting. Aminoglycoside modifying enzymes catalyze the modification at different -OH or -NH2 groups of the 2-deoxystreptamine nucleus or the sugar moieties and can be nucleotidyltranferases, phosphotransferases, or acetyltransferases. The no. of aminoglycoside modifying enzymes identified to date as well as the genetic environments where the coding genes are located is impressive and there is virtually no bacteria that is unable to support enzymic resistance to aminoglycosides. Aside from the development of new aminoglycosides refractory to as many as possible modifying enzymes there are currently two main strategies being pursued to overcome the action of aminoglycoside modifying enzymes. Their successful development would extend the useful life of existing antibiotics that have proven effective in the treatment of infections. These strategies consist of the development of inhibitors of the enzymic action or of the expression of the modifying enzymes.
29. 29
  Garneau-Tsodikova, S. and Labby, K. J. (2016) Mechanisms of Resistance to Aminoglycoside Antibiotics: Overview and Perspectives. MedChemComm 7, 11– 27, DOI: 10.1039/C5MD00344J
  29
  Mechanisms of resistance to aminoglycoside antibiotics: overview and perspectives
  Garneau-Tsodikova, Sylvie; Labby, Kristin J.
  MedChemComm (2016), 7 (1), 11-27CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
  A review. Aminoglycoside (AG) antibiotics are used to treat many Gram-neg. and some Gram-pos. infections and, importantly, multidrug-resistant tuberculosis. Among various bacterial species, resistance to AGs arises through a variety of intrinsic and acquired mechanisms. The bacterial cell wall serves as a natural barrier for small mols. such as AGs and may be further fortified via acquired mutations. Efflux pumps work to expel AGs from bacterial cells, and modifications here too may cause further resistance to AGs. Mutations in the ribosomal target of AGs, while rare, also contribute to resistance. Of growing clin. prominence is resistance caused by ribosome methyltransferases. By far the most widespread mechanism of resistance to AGs is the inactivation of these antibiotics by AG-modifying enzymes. We provide here an overview of these mechanisms by which bacteria become resistant to AGs and discuss their prevalence and potential for clin. relevance.
30. 30
  Bacot-Davis, V. R., Bassenden, A. V., and Berghuis, A. M. (2016) Drug-target Networks in Aminoglycoside Resistance: Hierarchy of Priority in Structural Drug Design. MedChemComm 7, 103– 113, DOI: 10.1039/C5MD00384A
  30
  Drug-target networks in aminoglycoside resistance: hierarchy of priority in structural drug design
  Bacot-Davis, Valjean R.; Bassenden, Angelia V.; Berghuis, Albert M.
  MedChemComm (2016), 7 (1), 103-113CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
  Antibiotic resistance is a multifactorial problem that demands multifaceted strategies to address. Here we present a drug-target network anal. of the clin. most prominent mechanism of resistance to aminoglycoside antibiotics, i.e. enzyme mediated modification of the antibiotics. This drug-target network displays prominent resistance preferences for 4,6-disubstituted aminoglycosides such as tobramycin and gentamicin, reflective of their extensive clin. usage. Further anal. also highlights aminoglycosides that remain more resilient to modifications by various bacterial resistance enzymes. This aminoglycoside resistance drug-target network conveys a compelling case for prioritization of next-generation aminoglycosides development exploiting 4,5-disubstituted and non-deoxystreptamine aminoglycoside scaffolds to surmount rising drug-resistance, in conjunction with advancing inhibitor/adjuvant leads effective against multiple aminoglycoside modifying enzyme.
31. 31
  Doi, Y., Wachino, J. I., and Arakawa, Y. (2016) Aminoglycoside Resistance: The Emergence of Acquired 16S Ribosomal RNA Methyltransferases. Infect. Dis. Clin. North Am. 30, 523– 537, DOI: 10.1016/j.idc.2016.02.011
  31
  Aminoglycoside Resistance: The Emergence of Acquired 16S Ribosomal RNA Methyltransferases
  Doi Yohei; Wachino Jun-Ichi; Arakawa Yoshichika
  Infectious disease clinics of North America (2016), 30 (2), 523-537 ISSN:.
  Aminoglycoside-producing Actinobacteria are known to protect themselves from their own aminoglycoside metabolites by producing 16S ribosomal RNA methyltransferase (16S-RMTase), which prevents them from binding to the 16S rRNA targets. Ten acquired 16S-RMTases have been reported from gram-negative pathogens. Most of them posttranscriptionally methylate residue G1405 of 16S rRNA resulting in high-level resistance to gentamicin, tobramycin, amikacin, and plazomicin. Strains that produce 16S-RMTase are frequently multidrug-resistant or even extensively drug-resistant. Although the direct clinical impact of high-level aminoglycoside resistance resulting from production of 16S-RMTase is yet to be determined, ongoing spread of this mechanism will further limit treatment options for multidrug-resistant and extensively drug-resistant gram-negative infections.
32. 32
  Sonousi, A., Sarpe, V. A., Brilkova, M., Schacht, J., Vasella, A., Böttger, E. C., and Crich, D. (2018) Effects of the 1-N-(4-Amino-2S-hydroxybutyryl) and 6′-N-(2-Hydroxyethyl) Substituents on Ribosomal Selectivity, Cochleotoxicity and Antibacterial Activity in the Sisomicin Class of Aminoglycoside Antibiotics. ACS Infect. Dis. 4, 1114– 1120, DOI: 10.1021/acsinfecdis.8b00052
  32
  Effects of the 1-N-(4-Amino-2S-hydroxybutyryl) and 6'-N-(2-Hydroxyethyl) Substituents on Ribosomal Selectivity, Cochleotoxicity, and Antibacterial Activity in the Sisomicin Class of Aminoglycoside Antibiotics
  Sonousi, Amr; Sarpe, Vikram A.; Brilkova, Margarita; Schacht, Jochen; Vasella, Andrea; Bottger, Erik C.; Crich, David
  ACS Infectious Diseases (2018), 4 (7), 1114-1120CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)
  Syntheses of the 6'-N-(2-hydroxyethyl) and 1-N-(4-amino-2S-hydroxybutyryl) derivs. of the 4,6-aminoglycoside sisomicin and that of the doubly modified 1-N-(4-amino-2S-hydroxybutyryl)-6'-N-(2-hydroxyethyl) deriv. known as plazomicin are reported together with their antibacterial and antiribosomal activities and selectivities. The 6'-N-(2-hydroxyethyl) modification results in a moderate increase in prokaryotic/eukaryotic ribosomal selectivity, whereas the 1-N-(4-amino-2S-hydroxybutyryl) modification has the opposite effect. When combined in plazomicin the effects of the two groups on ribosomal selectivity are cancelled leading to the prediction that plazomicin will exhibit comparable ototoxicity to the parent and to the current clin. AGAs gentamicin and tobramycin, as borne out by ex-vivo studies with mouse cochlear ex-plants. The 6'-N-(2-hydroxyethyl) modification restores antibacterial activity in the presence of the AAC(6') aminoglycoside-modifying enzymes, while the 1-N-(4-amino-2S-hydroxybutyryl) modification overcomes resistance to the AAC(2') class, but is still affected by the AAC(3) class. Neither modification is able to circumvent the ArmA ribosomal methyltransferase-induced aminoglycoside resistance. The use of phenyltriazenyl protection for the secondary amino group of sisomicin facilitates synthesis of each deriv. and their characterization through the provision of sharp NMR spectra for all intermediates.
33. 33
  Livermore, D. M., Mushtaq, S., Warner, M., Zhang, J.-C., Maharjan, S., Doumith, M., and Woodford, N. (2011) Activity of Aminoglycosides, Including ACHN-490, Against Carbapenem-resistant Enterobacteriaceae Isolates. J. Antimicrob. Chemother. 66, 48– 53, DOI: 10.1093/jac/dkq408
  33
  Activity of aminoglycosides, including ACHN-490, against carbapenem-resistant Enterobacteriaceae isolates
  Livermore, D. M.; Mushtaq, S.; Warner, M.; Zhang, J.-C.; Maharjan, S.; Doumith, M.; Woodford, N.
  Journal of Antimicrobial Chemotherapy (2011), 66 (1), 48-53CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
  The emergence of carbapenemases in Enterobacteriaceae is driving a search for therapeutic alternatives. The authors tested ACHN-490, a sisomicin deriv. that evades all plasmid-mediated aminoglycoside-modifying enzymes, against 82 carbapenem-resistant Enterobacteriaceae isolates. Comparators included internationally and locally available aminoglycosides. The isolates variously had KPC (n = 12), SME-1 (n = 1), IMP (n = 13), VIM (n = 5), NDM (n = 17) or OXA-48 (n = 19) carbapenemases, or had combinations of impermeability with AmpC (n = 5) or extended-spectrum β-lactamases (n = 10). They included 53 Klebsiella spp., 19 Enterobacter spp., 6 Escherichia coli and 4 others; most were multiresistant. Genes were identified by PCR and sequencing; MICs were measured by CLSI agar diln. ACHN-490 was active at ≤2 mg/L against all 65 isolates with carbapenem resistance mechanisms other than NDM enzyme, mostly with MICs of 0.12-0.5 mg/L; isepamicin was active against 63/65 at ≤8 mg/L. In contrast, 35% were resistant to gentamicin at 4 mg/L, 61% to tobramycin at 4 mg/L and 20% to amikacin at 16 mg/L. However, 16 of the 17 isolates with NDM-1 enzyme were resistant to ACHN-490, with MICs ≥64 mg/L, and these were cross-resistant to all other human-use aminoglycosides tested. Their behavior was assocd. with ArmA and RmtC 16S rRNA methylases. Apramycin (a veterinary aminoglycoside) retained its full activity, with MICs of 4-8 mg/L vs. strains with armA or rmtC, though resistance was seen in one Klebsiella pneumoniae with AAC(3)-IV (MIC ≥256 mg/L). ACHN-490 has potent activity vs. carbapenem-resistant isolates, except those also harboring 16S rRNA methylases; isepamicin is also widely active, though less potent than ACHN-490. Evasion of 16S rRNA methylases by apramycin is noteworthy and may provide a starting point for future aminoglycoside development.
34. 34
  Taylor, E., Sriskandan, S., Woodford, N., and Hopkins, K. L. (2018) High Prevalence of 16S rRNA Methyltransferases Among Carbapenenase-producing Enterobacteriaceae in the UK and Ireland. Int. J. Antimicrob. Agents 52, 278– 282, DOI: 10.1016/j.ijantimicag.2018.03.016
  34
  High prevalence of 16S rRNA methyltransferases among carbapenemase-producing Enterobacteriaceae in the UK and Ireland
  Taylor, Emma; Sriskandan, Shiranee; Woodford, Neil; Hopkins, Katie L.
  International Journal of Antimicrobial Agents (2018), 52 (2), 278-282CODEN: IAAGEA; ISSN:0924-8579. (Elsevier B.V.)
  The emergence of 16S rRNA methyltransferases (16S RMTases) worldwide is a growing concern due to their ability to confer high-level resistance (min. inhibitory concns. (MICs) >256 mg/L) to all clin. relevant aminoglycosides. As the occurrence of 16S RMTases in the United Kingdom has not been investigated to date, we screened 806 Enterobacteriaceae isolates displaying high-level aminoglycoside resistance (amikacin, gentamicin and tobramycin MICs ≥64, ≥32 and ≥32 mg/L, resp.) for 16S RMTases either by analyzing whole-genome sequence (WGS) data (which were available for 449 isolates) or by polymerase chain reaction. A total of 94.5% (762/806) pan-aminoglycoside-resistant Enterobacteriaceae were pos. for one or more 16S RMTase genes; armA was the most common (340, 44.6%) followed by rmtC (146, 19.2%), rmtF (137, 18.0%), rmtB (87, 11.4%) and various two-gene combinations (52, 6.8%). Most (93.4%; 712/762) 16S RMTase producers also carried acquired carbapenemase genes, with blaNDM the most common (592/712; 83.1%). Addnl., high-risk bacterial clones assocd. with blaNDM were identified in the subset of isolates with WGS data. These included Escherichia coli sequence types (STs) 405 (21.8%, 19/87), 167 (20.7%, 18/87) 410 (12.6%, 11/87) and K. pneumoniae STs 14 (35.6%, 112/315), 231 (15.6%, 49/315) and 147 (10.5%, 33/315). These accounted for 4.2% (15/358), 5.0% (18/358), 3.1% (11/358), 28.2% (101/358), 3.1% (11/358) and 7.0% (25/358) blaNDM-producing isolates, resp. This study shows that 16S RMTases occur in the UK and Ireland and carbapenemases are particularly prevalent in 16S RMTase-producing Enterobacteriaceae. This assocn. poses a risk to the treatment of multidrug-resistant Gram-neg. infections in the clin. setting.
35. 35
  Piekarska, K., Zacharczuk, K., Wołkowicz, T., Rzeczkowska, M., Bareja, E., Olak, M., and Gierczyński, R. (2016) Distribution of 16S rRNA Methylases Among Different Species of Aminoglycoside-Resistant Enterobacteriaceae in a Tertiary Care Hospital in Poland. Adv. Clin. Exp. Med. 25, 539– 544, DOI: 10.17219/acem/34150
  35
  Distribution of 16S rRNA Methylases Among Different Species of Aminoglycoside-Resistant Enterobacteriaceae in a Tertiary Care Hospital in Poland
  Piekarska Katarzyna; Zacharczuk Katarzyna; Wolkowicz Tomasz; Rzeczkowska Magdalena; Gierczynski Rafal; Bareja Elzbieta; Olak Monika
  Advances in clinical and experimental medicine : official organ Wroclaw Medical University (2016), 25 (3), 539-44 ISSN:1899-5276.
  BACKGROUND: Aminoglycosides are a group of antimicrobial agents still the most commonly used in the treatment of life-threatening bacterial infections in human and animals. The emergence and spread of 16S rRNA methylases, which confer high-level resistance to the majority of clinically relevant aminoglycosides, constitute a major public health concern. OBJECTIVES: Our goal was to evaluate the distribution of 16S rRNA methylases among different species of Enterobacteriaceae during a five month-long survey in a tertiary hospital in Warszawa, Poland. MATERIAL AND METHODS: In the survey, a total of 1770 non-duplicate clinical isolates were collected from all hospital wards in a tertiary hospital in Warszawa, Poland. The survey was conducted between 19 April and 19 September 2010. The ability to produce 16S rRNA methylase was examined by determining MICs for gentamicin, kanamycin, amikacin by means of the agar dilution method. The isolates resistant to high concentration of aminoglycosides were PCR tested for genes: armA, rmtA, rmtB and rmtC. PCR products were subjected to DNA sequencing by the Sanger method. The genetic similarity of the ArmA-producing isolates was analysed by pulsed-filed gel electrophoresis (PFGE). RESULTS: ArmA was the only 16S rRNA methylase detected in 20 of 1770 tested isolates. The overall prevalence rate of ArmA was 1.13%. In K. pneumoniae (n = 742), P. mirabilis (n = 130), and E. cloacae (n = 253) collected in the survey, the prevalence of ArmA was 0.4%, 0.8% and 5.9%, respectively. The PFGE revealed both horizontal and clonal spread of the armA gene in the hospital. CONCLUSIONS: The prevalence of 16S rRNA methylase ArmA reported in this study is significantly higher than observed in other countries in Europe.
36. 36
  Vicens, Q. and Westhof, E. (2003) Molecular Recognition of Aminoglycoside Antibiotics by Ribosomal RNA and Resistance Enzymes: An Analysis of X-Ray Crystal Structures. Biopolymers 70, 42– 57, DOI: 10.1002/bip.10414
  36
  Molecular recognition of aminoglycoside antibiotics by ribosomal RNA and resistance enzymes: An analysis of X-ray crystal structures
  Vicens, Quentin; Westhof, Eric
  Biopolymers (2003), 70 (1), 42-57CODEN: BIPMAA; ISSN:0006-3525. (John Wiley & Sons, Inc.)
  A review. The potential of RNA mols. to be used as therapeutic targets by small inhibitors is now well established. In this fascinating wide-open field, aminoglycoside antibiotics constitute the most studied family of RNA binding drugs. Within the last three years, several x-ray crystal structures were solved for aminoglycosides complexed to one of their main natural targets in the bacterial cell, the decoding aminoacyl-tRNA site (A site). Other crystallog. structures have revealed the binding modes of aminoglycosides to the three existing types of resistance-assocd. enzymes. The present review summarizes the various aspects of the mol. recognition of aminoglycosides by these natural RNA or protein receptors. The anal. and the comparisons of the detailed interactions offer insights that are helpful in designing new generations of antibiotics.
37. 37
  O’Connor, S., Lam, L. K. T., Jones, N. D., and Chaney, M. O. (1976) Apramycin, a Unique Aminocyclitol Antibiotic. J. Org. Chem. 41, 2087– 2092, DOI: 10.1021/jo00874a003
  37
  Apramycin, a unique aminocyclitol antibiotic
  O'Connor, Sean; Lam, L. K. T.; Jones, Noel D.; Chaney, Michael O.
  Journal of Organic Chemistry (1976), 41 (12), 2087-92CODEN: JOCEAH; ISSN:0022-3263.
  Apramycin produced by a strain of Streptomyces tenebrarius, does not fall into the tobramycin, kanamycin, gentamicin group and a detailed examination of its structure involving degradative, synthetic, and spectroscopic anal. leads to the assignment of the unusual structure I. The main features of which are a 4-amino-4-deoxy-D-glucose moiety, a 1-1' sugar linkage, and an octadiose which exists as a rigid bicyclic system. The proposed structure is confirmed by an x-ray diffraction study.
38. 38
  Smith, K. P. and Kirby, J. E. (2016) Evaluation of Apramycin Activity Against Carbapenem-Resistant and -Susceptible Strains of Enterobacteriaceae. Diagn. Microbiol. Infect. Dis. 86, 439– 441, DOI: 10.1016/j.diagmicrobio.2016.09.002
  38
  Evaluation of apramycin activity against carbapenem-resistant and -susceptible strains of Enterobacteriaceae
  Smith, Kenneth P.; Kirby, James E.
  Diagnostic Microbiology and Infectious Disease (2016), 86 (4), 439-441CODEN: DMIDDZ; ISSN:0732-8893. (Elsevier)
  We evaluated activity of apramycin, a non-ototoxic/non-nephrotoxic aminocyclitol against 141 clin. Enterobacteriaceae isolates, 51% of which were non-susceptible to carbapenems (CRE). Among CRE, 70.8% were apramycin susceptible, which compared favorably to aminoglycosides in current clin. use. Our data suggest that apramycin deserves further investigation as a repurposed, anti-CRE therapeutic.
39. 39
  Hu, Y., Liu, L., Zhang, X., Feng, Y., and Zong, Z. (2017) In Vitro Activity of Neomycin, Streptomycin, Paromomycin and Apramycin Against Carbapenem-resistant Enterobacteriaceae Clinical Strains. Front. Microbiol. 8, 2275, DOI: 10.3389/fmicb.2017.02275
  39
  In Vitro Activity of Neomycin, Streptomycin, Paromomycin and Apramycin against Carbapenem-Resistant Enterobacteriaceae Clinical Strains
  Hu Ya; Liu Lu; Zhang Xiaoxia; Feng Yu; Zong Zhiyong; Hu Ya; Liu Lu; Zhang Xiaoxia; Feng Yu; Zong Zhiyong; Zong Zhiyong; Zong Zhiyong
  Frontiers in microbiology (2017), 8 (), 2275 ISSN:1664-302X.
  We determined the in vitro susceptibility of four aminoglycosides, which are not of the 4,6-disubstituted deoxystreptamine (DOS) subclass against a collection of carbapenem-resistant Enterobacteriaceae (CRE). CRE clinical strains (n = 134) were collected from multiple hospitals in China and carried blaNDM (blaNDM-1, blaNDM-5 or blaNDM-7; n = 66), blaKPC-2 (n = 62) or blaIMP-4 (n = 7; including one carrying blaNDM-1 and blaIMP-4). MICs of neomycin, paromomycin, streptomycin and apramycin as well as three 4,6-disubstituted DOS aminoglycosides (amikacin, gentamicin and tobramycin) were determined using the broth microdilution with breakpoints defined by the Clinical Laboratory Standards Institute (for amikacin, gentamicin and tobramycin), US Food and Drug Administration (streptomycin), the National Antimicrobial Resistance Monitoring System (apramycin) or la Societe Francaise de Microbiologie (neomycin and paromomycin). Apramycin-resistant strains were subjected to whole genome sequencing using Illumina X10 platform. Among CRE strains, 65.7, 64.9, 79.1, and 95.5% were susceptible to neomycin (MIC50/MIC90, 8/256 μg/ml), paromomycin (4/>256 μg/ml), streptomycin (16/256 μg/ml) and apramycin (4/8 μg/ml), respectively, while only 55.2, 28.4, and 35.1% were susceptible to amikacin (32/>256 μg/ml), gentamicin (128/>256 μg/ml) and tobramycin (64/>256 μg/ml), respectively. Six CRE strains including five Escherichia coli of different sequence types and one Klebsiella pneumoniae were resistant to apramycin and the apramycin-resistant gene aac(3)-IVa was detected in all of these strains. In conclusion, neomycin, paromomycin, streptomycin and apramycin retain activity against most CRE strains. Although none of these non-4,6-disubstituted DOS aminoglycosides are suitable for intravenous use in human at present, these agents warrant further investigations to be used against CRE infections.
40. 40
  Kang, A. D., Smith, K. P., Eliopoulos, G. M., Berg, A. H., McCoy, C., and Kirby, J. E. (2017) In vitro Apramycin Activity Against Multidrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa. Diagn. Microbiol. Infect. Dis. 88, 188– 191, DOI: 10.1016/j.diagmicrobio.2017.03.006
  40
  Invitro Apramycin Activity against multidrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa
  Kang, Anthony D.; Smith, Kenneth P.; Eliopoulos, George M.; Berg, Anders H.; McCoy, Christopher; Kirby, James E.
  Diagnostic Microbiology and Infectious Disease (2017), 88 (2), 188-191CODEN: DMIDDZ; ISSN:0732-8893. (Elsevier)
  The in vitro activity of apramycin was compared to that of amikacin, gentamicin, and tobramycin against multidrug-resistant, extensively drug-resistant, and pandrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa. Apramycin demonstrated an MIC50/MIC90 of 8/32 μg/mL for A. baumannii and 16/32 μg/mL for P. aeruginosa. Only 2% of A. baumannii and P. aeruginosa had an MIC greater than an epidemiol. cutoff value of 64 μg/mL. In contrast, the MIC50/MIC90 for amikacin, gentamicin, and tobramycin were ≥64/>256 μg/mL for A. baumannii with 57%, 95%, and 74% of isolates demonstrating resistance, resp., and the MIC50/MIC90 were ≥8/256 μg/mL for P. aeruginosa with 27%, 50%, and 57% of strains demonstrating resistance, resp. Apramycin appears to offer promising in vitro activity against highly resistant pathogens. It therefore may warrant further pre-clin. study to assess potential for repurposing as a human therapeutic and relevance as a scaffold for further medicinal chem. exploration.
41. 41
  Juhas, M., Widlake, E., Teo, J., Huseby, D. L., Tyrrell, J. M., Polikanov, Y., Ercan, O., Petersson, A., Cao, S., Aboklaish, A. F., Rominski, A., Crich, D., Böttger, E. C., Walsh, T. R., Hughes, D. E., and Hobbie, S. N. (2019) In-vitro Activity of Apramycin Against Multidrug-, Carbapenem-, and Aminoglycoside-Resistant Enterobacteriaceae and Acinetobacter baumannii. J. Antimicrob. Chemother. 74, 944– 952, DOI: 10.1093/jac/dky546
  41
  In vitro activity of apramycin against multidrug-, carbapenem- and aminoglycoside-resistant Enterobacteriaceae and Acinetobacter baumannii
  Juhas, Mario; Widlake, Emma; Teo, Jeanette; Huseby, Douglas L.; Tyrrell, Jonathan M.; Polikanov, Yury S.; Ercan, Onur; Petersson, Anna; Cao, Sha; Aboklaish, Ali F.; Rominski, Anna; Crich, David; Bottger, Erik C.; Walsh, Timothy R.; Hughes, Diarmaid; Hobbie, Sven N.
  Journal of Antimicrobial Chemotherapy (2019), 74 (4), 944-952CODEN: JACHDX; ISSN:1460-2091. (Oxford University Press)
  Objectives: Widespread antimicrobial resistance often limits the availability of therapeutic options to only a few last-resort drugs that are themselves challenged by emerging resistance and adverse side effects. Apramycin, an aminoglycoside antibiotic, has a unique chem. structure that evades almost all resistance mechanisms including the RNA methyltransferases frequently encountered in carbapenemase-producing clin. isolates. This study evaluates the in vitro activity of apramycin against multidrug-, carbapenem- and aminoglycoside-resistant Enterobacteriaceae and Acinetobacter baumannii, and provides a rationale for its superior antibacterial activity in the presence of aminoglycoside resistance determinants. Methods: A thorough antibacterial assessment of apramycin with 1232 clin. isolates from Europe, Asia, Africa and South America was performed by std. CLSI broth microdilution testing. WGS and susceptibility testing with an engineered panel of aminoglycoside resistance-conferring determinants were used to provide a mechanistic rationale for the breadth of apramycin activity. Results: MIC distributions and MIC90 values demonstrated broad antibacterial activity of apramycin against Escherichia coli, Klebsiella pneumoniae, Enterobacter spp., Morganella morganii, Citrobacter freundii, Providencia spp., Proteus mirabilis, Serratia marcescens and A. baumannii. Genotypic anal. revealed the variety of aminoglycoside-modifying enzymes and rRNA methyltransferases that rendered a remarkable proportion of clin. isolates resistant to std.-of-care aminoglycosides, but not to apramycin. Screening a panel of engineered strains each with a single well-defined resistance mechanism further demonstrated a lack of cross-resistance to gentamicin, amikacin, tobramycin and plazomicin. Conclusions: Its superior breadth of activity renders apramycin a promising drug candidate for the treatment of systemic Gram-neg. infections that are resistant to treatment with other aminoglycoside antibiotics.
42. 42
  (2018) Tackling Antimicrobial Resistance: ENABLE Selects First Clinical Candidate, Innovative Medicines Initiative. https://www.imi.europa.eu/projects-results/project-factsheets/enable (accessed Feb 12, 2019).
  There is no corresponding record for this reference.
43. 43
  Perez-Fernandez, D., Shcherbakov, D., Matt, T., Leong, N. C., Kudyba, I., Duscha, S., Boukari, H., Patak, R., Dubbaka, S. R., Lang, K., Meyer, M., Akbergenov, R., Freihofer, P., Vaddi, S., Thommes, P., Ramakrishnan, V., Vasella, A., and Böttger, E. C. (2014) 4′-O-Substitutions Determine Aminoglycoside Selectivity at the Drug Target Level. Nat. Commun. 5, 3112, DOI: 10.1038/ncomms4112
  43
  4'-O-substitutions determine selectivity of aminoglycoside antibiotics
  Perez-Fernandez Deborah; Shcherbakov Dmitri; Matt Tanja; Duscha Stefan; Boukari Heithem; Meyer Martin; Akbergenov Rashid; Freihofer Pietro; Bottger Erik C; Leong Ng Chyan; Kudyba Iwona; Patak Rashmi; Dubbaka Srinivas Reddy; Vasella Andrea; Lang Kathrin; Ramakrishnan V; Vaddi Swapna; Thommes Pia
  Nature communications (2014), 5 (), 3112 ISSN:.
  Clinical use of 2-deoxystreptamine aminoglycoside antibiotics, which target the bacterial ribosome, is compromised by adverse effects related to limited drug selectivity. Here we present a series of 4',6'-O-acetal and 4'-O-ether modifications on glucopyranosyl ring I of aminoglycosides. Chemical modifications were guided by measuring interactions between the compounds synthesized and ribosomes harbouring single point mutations in the drug-binding site, resulting in aminoglycosides that interact poorly with the drug-binding pocket of eukaryotic mitochondrial or cytosolic ribosomes. Yet, these compounds largely retain their inhibitory activity for bacterial ribosomes and show antibacterial activity. Our data indicate that 4'-O-substituted aminoglycosides possess increased selectivity towards bacterial ribosomes and little activity for any of the human drug-binding pockets.
44. 44
  Duscha, S., Boukari, H., Shcherbakov, D., Salian, S., Silva, S., Kendall, A., Kato, T., Akbergenov, R., Perez-Fernandez, D., Bernet, B., Vaddi, S., Thommes, P., Schacht, J., Crich, D., Vasella, A., and Böttger, E. C. (2014) Identification and Evaluation of Improved 4′-O-(Alkyl) 4,5-Disubstituted 2-Deoxystreptamines as Next Generation Aminoglycoside Antibiotics. mBio 5, e01827– 14, DOI: 10.1128/mBio.01827-14
  44
  Identification and evaluation of improved 4'-O-(Alkyl) 4,5-disubstituted 2-deoxystreptamines as next-generation aminoglycoside antibiotics
  Duscha, Stefan; Boukari, Heithem; Shcherbakov, Dimitri; Salian, Sumantha; Silva, Sandrina; Kendall, Ann; Kato, Takayuki; Akbergenov, Rashid; Perez-Fernandez, Deborah; Bernet, Bruno; Vaddi, Swapna; Thommes, Pia; Schacht, Jochen; Crich, David; Vasella, Andrea; Boettger, Erik C.
  mBio (2014), 5 (5), e01827-14/1-e01827-14/11CODEN: MBIOCL; ISSN:2150-7511. (American Society for Microbiology)
  The emerging epidemic of drug resistance places the development of efficacious and safe antibiotics in the spotlight of current research. Here, we report the design of next-generation aminoglycosides. Discovery efforts were driven by rational synthesis focusing on 4' alkylations of the aminoglycoside paromomycin, with the goal to alleviate the most severe and disabling side effect of aminoglycosides-irreversible hearing loss. Compds. were evaluated for target activity in in vitro ribosomal translation assays, antibacterial potency against selected pathogens, cytotoxicity against mammalian cells, and in vivo ototoxicity. The results of this study produced potent compds. with excellent selectivity at the ribosomal target, promising antibacterial activity, and little, if any, ototoxicity upon chronic administration. The favorable biocompatibility profile combined with the promising antibacterial activity emphasizes the potential of next-generation aminoglycosides in the treatment of infectious diseases without the risk of ototoxicity.
45. 45
  Matsushita, T., Chen, W., Juskeviciene, R., Teo, Y., Shcherbakov, D., Vasella, A., Böttger, E. C., and Crich, D. (2015) Influence of 4′-O-Glycoside Constitution and Configuration on Ribosomal Selectivity of Paromomycin. J. Am. Chem. Soc. 137, 7706– 7717, DOI: 10.1021/jacs.5b02248
  45
  Influence of 4'-O-Glycoside Constitution and Configuration on Ribosomal Selectivity of Paromomycin
  Matsushita, Takahiko; Chen, Weiwei; Juskeviciene, Reda; Teo, Youjin; Shcherbakov, Dimitri; Vasella, Andrea; Bottger, Erik C.; Crich, David
  Journal of the American Chemical Society (2015), 137 (24), 7706-7717CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  A series of 20 4'-O-glycosides of the aminoglycoside antibiotic paromomycin were synthesized and evaluated for their ability to inhibit protein synthesis by bacterial, mitochondrial and cytosolic ribosomes. Target selectivity, i.e., inhibition of the bacterial ribosome over eukaryotic mitochondrial and cytosolic ribosomes, which is predictive of antibacterial activity with reduced ototoxicity and systemic toxicity, was greater for the equatorial than for the axial pyranosides, and greater for the D-pentopyranosides than for the L-pentopyranosides and D-hexopyranosides. In particular, 4'-O-β-D-xylopyranosyl paromomycin shows antibacterial ribosomal activity comparable to that of paromomycin, but is significantly more selective showing considerably reduced affinity for the cytosolic ribosome and for the A1555G mutant mitochondrial ribosome assocd. with hyper-susceptibility to drug-induced ototoxicity. Compd. antibacterial ribosomal activity correlates with antibacterial activity, and the ribosomally more active compds. show activity against Escherichia coli, Klebsiella pneumonia, Enterobacter cloacae, Acinetobacter baumannii, and methicillin-resistant Staphylococcus aureus (MRSA). The paromomycin glycosides retain activity against clin. strains of MRSA that are resistant to paromomycin, which is demonstrated to be a consequence of 4'-O-glycosylation blocking the action of 4'-aminoglycoside nucleotidyl transferases by the use of recombinant E. coli carrying the specific resistance determinant.
46. 46
  Sati, G. C., Shcherbakov, D., Hobbie, S., Vasella, A., Böttger, E. C., and Crich, D. (2017) N6′, N6‴, and O4′-Modifications to Neomycin Affect Ribosomal Selectivity Without Compromising Antibacterial Activity. ACS Infect. Dis. 3, 368– 376, DOI: 10.1021/acsinfecdis.6b00214
  46
  N6', N6''', and O4' Modifications to Neomycin Affect Ribosomal Selectivity without Compromising Antibacterial Activity
  Sati, Girish C.; Shcherbakov, Dimitri; Hobbie, Sven N.; Vasella, Andrea; Bottger, Erik C.; Crich, David
  ACS Infectious Diseases (2017), 3 (5), 368-377CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)
  The synthesis of a series of neomycin derivs. carrying the 2-hydroxyethyl substituent on N6' and/or N6''' both alone and in combination with a 4'-O-Et group is described. By means of cell-free translation assays with wild-type bacterial ribosomes and their hybrids with eukaryotic decoding A sites, we investigate how individual substituents and their combinations affect activity and selectivity at the target level. In principle, and as shown by cell-free translation assays, modifications of the N6' and N6''' positions allow to enhance target selectivity without compromising antibacterial activity. As with the 6'OH paromomycin, the 4'-O-Et modification further affects the ribosomal activity, selectivity, and antibacterial profile of neomycin and its 6'-N-(2-hydroxyethyl) derivs. The modified aminoglycosides show good antibacterial activity against model Gram-pos. and Gram-neg. microbes including the ESKAPE pathogens S. aureus, K. pneumoniae, E. cloacae, and A. baumannii.
47. 47
  Matsushita, T., Sati, G. C., Kondasinghe, N., Pirrone, M. G., Kato, T., Waduge, P., Kumar, H. S., Cortes Sanchon, A., Dobosz-Bartoszek, M., Shcherbakov, D., Juhas, M., Hobbie, S. N., Schrepfer, T., Chow, C. S., Polikanov, Y. S., Schacht, J., Vasella, A., Böttger, E. C., and Crich, D. (2019) Design, Multigram Synthesis, and in Vitro and in Vivo Evaluation of Propylamycin: A Semisynthetic 4,5-Deoxystreptamine Class Aminoglycoside for the Treatment of Drug-Resistant Enterobacteriaceae and Other Gram-Negative Pathogens. J. Am. Chem. Soc. 141, 5051– 5061, DOI: 10.1021/jacs.9b01693
  47
  Design, Multigram Synthesis, and in Vitro and in Vivo Evaluation of Propylamycin: A Semisynthetic 4,5-Deoxystreptamine Class Aminoglycoside for the Treatment of Drug-Resistant Enterobacteriaceae and Other Gram-Negative Pathogens
  Matsushita, Takahiko; Sati, Girish C.; Kondasinghe, Nuwan; Pirrone, Michael G.; Kato, Takayuki; Waduge, Prabuddha; Kumar, Harshitha Santhosh; Sanchon, Adrian Cortes; Dobosz-Bartoszek, Malgorzata; Shcherbakov, Dimitri; Juhas, Mario; Hobbie, Sven N.; Schrepfer, Thomas; Chow, Christine S.; Polikanov, Yury S.; Schacht, Jochen; Vasella, Andrea; Bottger, Erik C.; Crich, David
  Journal of the American Chemical Society (2019), 141 (12), 5051-5061CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  Infectious diseases due to multidrug-resistant pathogens, particularly carbapenem-resistant Enterobacteriaceae (CREs), present a major and growing threat to human health and society, providing an urgent need for the development of improved potent antibiotics for their treatment. We describe the design and development of a new class of aminoglycoside antibiotics culminating in the discovery of propylamycin. Propylamycin is a 4'-deoxy-4'-alkyl paromomycin whose alkyl substituent conveys excellent activity against a broad spectrum of ESKAPE pathogens and other Gram-neg. infections, including CREs, in the presence of numerous common resistance determinants, be they aminoglycoside modifying enzymes or rRNA Me transferases. Importantly, propylamycin is demonstrated not to be susceptible to the action of the ArmA resistance determinant whose presence severely compromises the action of plazomicin and all other 4,6-disubstituted 2-deoxystreptamine aminoglycosides. The lack of susceptibility to ArmA, which is frequently encoded on the same plasmid as carbapenemase genes, ensures that propylamycin will not suffer from problems of cross-resistance when used in combination with carbapenems. Cell-free translation assays, quant. ribosome footprinting, and X-ray crystallog. support a model in which propylamycin functions by interference with bacterial protein synthesis. Cell-free translation assays with humanized bacterial ribosomes were used to optimize the selectivity of propylamycin, resulting in reduced ototoxicity in guinea pigs. In mouse thigh and septicemia models of Escherichia coli, propylamycin shows excellent efficacy, which is better than paromomycin. Overall, a simple novel deoxy alkyl modification of a readily available aminoglycoside antibiotic increases the inherent antibacterial activity, effectively combats multiple mechanisms of aminoglycoside resistance, and minimizes one of the major side effects of aminoglycoside therapy.
48. 48
  Böttger, E. C. and Schacht, J. (2013) The Mitochondrion: A Perpetrator of Acquired Hearing Loss. Hear. Res. 303, 12– 19, DOI: 10.1016/j.heares.2013.01.006
  48
  The mitochondrion: A perpetrator of acquired hearing loss
  Bottger, Erik C.; Schacht, Jochen
  Hearing Research (2013), 303 (), 12-19CODEN: HERED3; ISSN:0378-5955. (Elsevier B.V.)
  A review. Age, drugs, and noise are major causes of acquired hearing loss. The involvement of reactive oxygen species (ROS) in hair cell death has long been discussed, but there is considerably less information available as to the mechanisms underlying ROS formation. Most cellular ROS arise in mitochondria and this review will evaluate evidence for mitochondrial pathol. in general and dysfunction of the mitochondrial respiratory chain in particular in acquired hearing loss. We will discuss evidence that different pathways can lead to the generation of ROS and that oxidative stress might not necessarily be causal to all three pathologies. Finally, we will detail recent advances in exploiting knowledge of aminoglycoside-mitochondria interactions for the development of non-ototoxic antibacterials.This article is part of a Special Issue entitled "Annual Reviews 2013".
49. 49
  Huth, M. E., Ricci, A. J., and Cheng, A. G. (2011) Mechanisms of Aminoglycoside Ototoxicity and Targets of Hair Cell Protection. Int. J. Otolaryngol. 2011, 937861, DOI: 10.1155/2011/937861
  49
  Mechanisms of aminoglycoside ototoxicity and targets of hair cell protection
  Huth M E; Ricci A J; Cheng A G
  International journal of otolaryngology (2011), 2011 (), 937861 ISSN:.
  Aminoglycosides are commonly prescribed antibiotics with deleterious side effects to the inner ear. Due to their popular application as a result of their potent antimicrobial activities, many efforts have been undertaken to prevent aminoglycoside ototoxicity. Over the years, understanding of the antimicrobial as well as ototoxic mechanisms of aminoglycosides has increased. These mechanisms are reviewed in regard to established and potential future targets of hair cell protection.
50. 50
  Jiang, M., Karasawa, T., and Steyger, P. S. (2017) Aminoglycoside-Induced Cochleotoxicity: A Review. Front. Cell. Neurosci. 11, 308, DOI: 10.3389/fncel.2017.00308
  50
  Aminoglycoside-induced cochleotoxicity: a review
  Jiang, Meiyan; Karasawa, Takatoshi; Steyger, Peter S.
  Frontiers in Cellular Neuroscience (2017), 11 (), 308/1-308/14CODEN: FCNRAH; ISSN:1662-5102. (Frontiers Media S.A.)
  Aminoglycoside antibiotics are used as prophylaxis, or urgent treatment, for many life-threatening bacterial infections, including tuberculosis, sepsis, respiratory infections in cystic fibrosis, complex urinary tract infections and endocarditis. Although aminoglycosides are clin.-essential antibiotics, the mechanisms underlying their selective toxicity to the kidney and inner ear continue to be unraveled despite more than 70 years of investigation. The following mechanisms each contribute to aminoglycoside-induced toxicity after systemic administration: (1) drug trafficking across endothelial and epithelial barrier layers; (2) sensory cell uptake of these drugs; and (3) disruption of intracellular physiol. pathways. Specific factors can increase the risk of drug-induced toxicity, including sustained exposure to higher levels of ambient sound, and selected therapeutic agents such as loop diuretics and glycopeptides. Serious bacterial infections (requiring life-saving aminoglycoside treatment) induce systemic inflammatory responses that also potentiate the degree of ototoxicity and permanent hearing loss. We discuss prospective clin. strategies to protect auditory and vestibular function from aminoglycoside ototoxicity, including reduced cochlear or sensory cell uptake of aminoglycosides, and otoprotection by ameliorating intracellular cytotoxicity.
51. 51
  Cassinelli, G., Franceschi, G., Di Colo, G., and Arcamone, F. (1978) Semisynthetic Aminoglycoside Antibiotics 1. New Reactions of Paromomycin and Synthesis of its 2′-N-Ethyl Derivative. J. Antibiot. 31, 378– 381, DOI: 10.7164/antibiotics.31.379
  There is no corresponding record for this reference.
52. 52
  Cassinelli, G., Julita, P., and Arcamone, F. (1978) Semisynthetic Aminoglycoside Antibiotics II. Synthesis of Analogues of Paromomycin Modified in the Glucosamine Moiety. J. Antibiot. 31, 382– 384, DOI: 10.7164/antibiotics.31.382
  52
  Semisynthetic aminoglycoside antibiotics. II. Synthesis of analogs of paromomycin modified in the glucosamine moiety
  Cassinelli, Giuseppe; Julita, Piera; Arcamone, Federico
  Journal of Antibiotics (1978), 31 (4), 382-4CODEN: JANTAJ; ISSN:0021-8820.
  Aminoglycosides I, II, and III were prepd. from 1,3,2''',6'''-tetra-N-acetylparomomycin by a series of known reactions via IV as the key intermediate. Reaction of IV with dimer of 3,4-di-O-acetyl-2-deoxy-2-nitroso-6-O-tosyl-α-D-glucopyranosyl chloride led to I and II in 6 and 2% overall yield, resp. Reaction of IV with dimer of 3,4-di-O-acetyl-2-deoxy-2-nitroso-6-O-tosyl-α-D-galactopyranosyl chloride led to III in 4% overall yield. In comparison with the antibacterial activity of paromomycin, I showed similar or slightly reduced potency against sensitive organisms and a two-fold increased activity against some resistant strains of gram-neg. bacteria, while II and III showed a weak antibacterial activity.
53. 53
  Roestamadji, J., Graspsas, I., and Mobashery, S. (1995) Loss of Individual Electrostatic Interactions between Aminoglycoside Antibiotics and Resistance Enzymes as an Effective Means to Overcoming Bacterial Drug Resistance. J. Am. Chem. Soc. 117, 11060– 11069, DOI: 10.1021/ja00150a004
  53
  Loss of individual electrostatic interactions between aminoglycoside antibiotics and resistance enzymes as an effective means to overcoming bacterial drug resistance
  Roestamadji, Juliatiek; Grapsas, Ioannis; Mobashery, Shahriar
  Journal of the American Chemical Society (1995), 117 (45), 11060-9CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  Aminoglycoside-modifying enzymes modify the structures of aminoglycoside antibiotics, rendering them ineffective, a process which confers resistance to the antibiotic. Electrostatic interactions (ion pairing and hydrogen bonding) are believed to be significant for both substrate recognition and catalysis by these enzymes. Regiospecific syntheses of 7 distinct deaminated analogs of neamine and kanamycin A (I, II, III, IV and V, VI, and VII, resp.), 2 aminoglycoside antibiotics, are described. Each of these compds. would have impaired interaction with a different subsite of the enzyme active sites. All 7 mols. were exceedingly poor substrates for 2 aminoglycoside-modifying enzymes, aminoglycoside 3'-phosphotransferases types Ia and IIa. The energetic contribution of interactions of the active-site functions with each of these amines on stabilization of the transition-state species has been evaluated to be in the range of 6-11 kcal/mol, the largest energy contribution recorded in the literature for such interactions. The biol. activities of these analogs were the same against the resistant organisms harboring aminoglycoside 3'-phosphotransferases types Ia and IIa as those against the background strain without the resistant enzymes. Thus, these compds. are virtually unmodified by those enzymes in vivo. The principles described here should be of general interest for circumvention of resistance to other antibiotics, by redesigning the structures to minimize electrostatic interactions with their corresponding resistance enzymes.
54. 54
  Ferrier, R. J., Hay, R. W., and Vethaviyasar, N. (1973) A Potentially Versatile Synthesis of Glycosides. Carbohydr. Res. 27, 55– 61, DOI: 10.1016/S0008-6215(00)82424-6
  54
  Potentially versatile synthesis of glycosides
  Ferrier, R. J.; Hay, R. W.; Vethaviyasar, N.
  Carbohydrate Research (1973), 27 (1), 55-61CODEN: CRBRAT; ISSN:0008-6215.
  Ph 1-thio-D-glucopyranosides in the presence of Hg(II) salts are readily solvolyzed to give alkyl D-glucopyranosides with inverted anomeric configuration. Methanolyses of the β and α anomers afford the Me α- and β-glycosides in yields of 74 and 87%, resp.; NMR examns. indicated that, whereas the β-glycoside was produced stereospecifically, the α-glycoside was formed together with ∼6% of its β isomer. The approach can be extended to the synthesis of complex glycosides as was illustrated by the prepn. of cholestanyl and 1-naphthyl α-D-glucopyranoside and a disaccharide deriv.
55. 55
  Greenberg, W. A., Priestley, E. S., Sears, P. S., Alper, P. B., Rosenbohm, C., Hendrix, M., Hung, S.-C., and Wong, C.-H. (1999) Design and Synthesis of New Aminoglycoside Antibiotics Containing Neamine as an Optimal Core Structure: Correlation of Antibiotic Activity with in Vitro Inhibition of Translation. J. Am. Chem. Soc. 121, 6527– 6541, DOI: 10.1021/ja9910356
  55
  Design and Synthesis of New Amino Glycoside Antibiotics Containing Neamine as an Optimal Core Structure: Correlation of Antibiotic Activity with in Vitro Inhibition of Translation
  Greenberg, William A.; Priestley, E. Scott; Sears, Pamela S.; Alper, Phil B.; Rosenbohm, Christoph; Hendrix, Martin; Hung, Shang-Cheng; Wong, Chi-Huey
  Journal of the American Chemical Society (1999), 121 (28), 6527-6541CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  The structure and activity of the pseudo-disaccharide core found in amino glycoside antibiotics was probed with a series of synthetic analogs in which the position of amino groups was varied around the glucopyranose ring. The naturally occurring structure neamine was the best in the series according to assays for in vitro RNA binding and antibiotic activity. With this result in hand, neamine was used as a common core structure for the synthesis of new antibiotics, which were evaluated for binding to models of the Escherichia coli 16S A-site rRNA, in vitro protein synthesis inhibition, and antibiotic activity. Anal. of RNA binding revealed some correlation between the relative affinity and specificity of RNA binding and antibacterial efficacy. However, the correlation was not linear. This result led us to develop the in vitro translation assay in an effort to better understand amino glycoside-RNA interactions. A linear correlation between in vitro translation inhibition and antibiotic activity was obsd. In addn., IC50s in the protein synthesis assay were typically lower than the Kds obtained for RNA binding, suggesting that binding of these compds. to intact ribosomes is tighter in these cases than binding to the model RNA oligodeoxyribonucleotides. This reflects possible differences in RNA conformation between intact ribosomes and the free RNA of the model system, or possible high-affinity ribosomal binding sites in addn. to the A-site RNA.
56. 56
  Lu, S.-R., Lai, Y. H., Chen, J.-H., Liu, C.-Y., and Mong, K.-K. T. (2011) Dimethylformamide: An Unusual Glycosylation Modulator. Angew. Chem., Int. Ed. 50, 7315– 7320, DOI: 10.1002/anie.201100076
  56
  Dimethylformamide: An Unusual Glycosylation Modulator
  Lu, Shao-Ru; Lai, Yen-Hsun; Chen, Jiun-Han; Liu, Chih-Yueh; Mong, Kwok-Kong Tony
  Angewandte Chemie, International Edition (2011), 50 (32), 7315-7320, S7315/1-S7315/125CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  When N,N-dimethylformamide was used to direct the stereochem. course of glycosylation reactions, 1,2-cis glycosylation products were formed with excellent selectivity. A straightforward highly α-stereoselective glycosylation involving preactivation should find broad application and be esp. useful for sequential glycosylation reactions to form oligosaccharides.
57. 57
  Saegusa, T., Kobayashi, S., Ito, Y., and Yasuda, N. (1968) Radical Reaction of Isocyanide with Organotin Hydride. J. Am. Chem. Soc. 90, 4182– 4182, DOI: 10.1021/ja01017a061
  57
  Radical reaction of isocyanide with organotin hydride
  Saegusa, Takeo; Kobayashi, Shiro; Ito, Yoshihiko; Yasuda, Naohiko
  Journal of the American Chemical Society (1968), 90 (15), 4182CODEN: JACSAT; ISSN:0002-7863.
  Isocyanides (RNC) and trialkyltin hydrides gave trialkyltin isocyanides and the hydrocarbon RH. In a typical reaction, PhCH2NC, Bu3SnH, and tert-Bu2O2 under N gave Bu3Sn (iso)cyanide, identical with the product from Bu3SnCl and KCN. A free radical mechanism is proposed.
58. 58
  Barton, D. H. R., Bringmann, G., Lamotte, G., Motherwell, W. B., Hay Motherwell, R. S., and Porter, A. E. A. (1980) Reactions of Relevance to the Chemistry of the Aminoglycoside Antibiotics. Part 14. A Useful Radical-Deamination Reaction. J. Chem. Soc., Perkin Trans. 1 1, 2657– 2664, DOI: 10.1039/p19800002657
  There is no corresponding record for this reference.
59. 59
  Barton, D. H. R., Bringmann, G., and Motherwell, W. B. (1980) Reactions of Relevance to the Aminoglycoside Antibiotics. Part 15. The Selective Modification of Neamine by Radical-Induced Deamination. J. Chem. Soc., Perkin Trans. 1 1, 2665– 2669, DOI: 10.1039/p19800002665
  There is no corresponding record for this reference.
60. 60
  Ballestri, M., Chatgilialoglu, C., Clark, K. B., Griller, D., Giese, B., and Kopping, B. (1991) Tris(trimethylsily1)silane as a Radical-Based Reducing Agent in Synthesis. J. Org. Chem. 56, 678– 683, DOI: 10.1021/jo00002a035
  60
  Tris(trimethylsilyl)silane as a radical-based reducing agent in synthesis
  Ballestri, M.; Chatgilialoglu, C.; Clark, K. B.; Griller, D.; Giese, B.; Kopping, B.
  Journal of Organic Chemistry (1991), 56 (2), 678-83CODEN: JOCEAH; ISSN:0022-3263.
  Tris(trimethylsilyl)silane is an effective reducing agent for org. halides, selenides, xanthates, and isocyanides, as well as an effective hydrosilylating agent for dialkyl ketones and alkenes. The silane functions as a mediator in the formation of intermol. carbon-carbon bonds via radicals and allows a variety of org. substrates to be used as alkyl radical precursors. Abs. rate consts. for the reaction of (Me3Si)3Si• radicals with a variety of org. compds. were measured in soln. by laser flash photolysis. At 294 K rate consts. are >5 × 107M-1 s-1 for C:C double bonds that are activated by neighboring π-electron systems or by electron-withdrawing groups. For other substrates, reactivities decreased in order xanthate > selenide > isocyanide > nitro > sulfide.
61. 61
  Goddard-Borger, E. D. and Stick, R. V. (2007) An Efficient, Inexpensive, and Shelf-Stable Diazotransfer Reagent: Imidazole-1-sulfonyl Azide Hydrochloride. Org. Lett. 9, 3797– 3800, DOI: 10.1021/ol701581g
  61
  An Efficient, Inexpensive, and Shelf-Stable Diazotransfer Reagent: Imidazole-1-sulfonyl Azide Hydrochloride
  Goddard-Borger, Ethan D.; Stick, Robert V.
  Organic Letters (2007), 9 (19), 3797-3800CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
  The design and synthesis of a new diazotransfer reagent, imidazole-1-sulfonyl azide hydrochloride, are reported. This reagent has proven to equal triflyl azide in its ability to act as a "diazo donor" in the conversion of both primary amines into azides and activated methylene substrates into diazo compds. Crucially, this reagent can be prepd. in a one-pot reaction on a large scale from inexpensive materials, is shelf-stable, and is conveniently cryst.
62. 62
  Ye, H., Liu, R., Li, D., Liu, Y., Yuan, H., Guo, W., Zhou, L., Cao, X., Tian, H., Shen, J., and Wang, P. G. (2013) A Safe and Facile Route to Imidazole-1-sulfonyl Azide as a Diazotransfer Reagent. Org. Lett. 15, 18– 21, DOI: 10.1021/ol3028708
  62
  A Safe and Facile Route to Imidazole-1-sulfonyl Azide as a Diazotransfer Reagent
  Ye, Hui; Liu, Ruihua; Li, Dongmei; Liu, Yonghui; Yuan, Haixin; Guo, Weikang; Zhou, Lifei; Cao, Xuefeng; Tian, Hongqi; Shen, Jie; Wang, Peng George
  Organic Letters (2013), 15 (1), 18-21CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
  A facile approach to the diazo-transfer reagent of imidazole-1-sulfonyl azide was reported. The procedure was well optimized to clarify potential explosion risks. A high prodn. yield as well as small batch variation was achieved even without careful pretreatment of reagents and solvents. HPLC and NMR methods to monitor the process were provided. These features made this protocol suitable for large scale prepn. in academia and industry as well.
63. 63
  Fischer, N., Goddard-Borger, E. D., Greiner, R., Klapotke, T. M., Skelton, B. W., and Stierstorfer, J. (2012) Senstivities of Some Imidazole-1-sulfonyl Azide Salts. J. Org. Chem. 77, 1760– 1764, DOI: 10.1021/jo202264r
  63
  Sensitivities of Some Imidazole-1-sulfonyl Azide Salts
  Fischer, Niko; Goddard-Borger, Ethan D.; Greiner, Robert; Klapoetke, Thomas M.; Skelton, Brian W.; Stierstorfer, Joerg
  Journal of Organic Chemistry (2012), 77 (4), 1760-1764CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  Imidazole-1-sulfonyl azide hydrochloride, an inexpensive and effective diazo transfer reagent, was recently found to be impact sensitive. To identify safer-to-handle forms of this reagent, several different salts of imidazole-1-sulfonyl azide were prepd., and their sensitivity to heat, impact, friction, and electrostatic discharge was quant. detd. A no. of these salts exhibited improved properties and can be considered safer than the aforementioned hydrochloride. The solid-state structures of the chloride and less sensitive hydrogen sulfate were detd. by single-crystal x-ray diffraction in an effort to provide some insight into the different properties of the materials.
64. 64
  Potter, G. T., Jayson, G. C., Miller, G. J., and Gardiner, J. M. (2016) An Updated Synthesis of the Diazo-Transfer Reagent Imidazole-1-sulfonyl Azide Hydrogen Sulfate. J. Org. Chem. 81, 3443– 3446, DOI: 10.1021/acs.joc.6b00177
  64
  An Updated Synthesis of the Diazo-Transfer Reagent Imidazole-1-sulfonyl Azide Hydrogen Sulfate
  Potter, Garrett T.; Jayson, Gordon C.; Miller, Gavin J.; Gardiner, John M.
  Journal of Organic Chemistry (2016), 81 (8), 3443-3446CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  Imidazole-1-sulfonyl azide and salts thereof are valuable reagents for diazo-transfer reactions, most particularly conversion of primary amines to azides. The parent reagent and its HCl salt present stability and detonation risks, but the hydrogen sulfate salt is significantly more stable. An updated procedure for the large-scale synthesis of this salt avoids isolation or concn. of the parent compd. or HCl salt and will facilitate the use of hydrogen sulfate salt as the reagent of choice for diazo transfer.
65. 65
  Flynn, D. L., Zelle, R. E., and Grieco, P. A. (1983) A Mild Two-Step Method for the Hydolysis/Methanolysis of Secondary Amides and Lactams. J. Org. Chem. 48, 2424– 2426, DOI: 10.1021/jo00162a028
  65
  A mild two-step method for the hydrolysis of lactams and secondary amides
  Flynn, Daniel L.; Zelle, Robert E.; Grieco, Paul A.
  Journal of Organic Chemistry (1983), 48 (14), 2424-6CODEN: JOCEAH; ISSN:0022-3263.
  We report herein that N-tert-Boc derivs. of lactams and amides, prepd. through the agency of di-tert-Bu dicarbonate, suffer regioselective hydrolysis employing LiOH or methanolysis under mild conditions leading to the corresponding ω-amino acids or esters, resp. N-(tert-Butoxycarbonyl)-γ-butyrolactam was stirred with LiOH at 25° and the mixt. was acidified to give Me3COC(O)NH(CH2)3CO2H.
66. 66
  Pathak, R., Perez-Fernandez, D., Nandurdikar, R., Kalapala, S. K., Böttger, E. C., and Vasella, A. (2008) Synthesis and Evaluation of Paromomycin Derivatives Modified at C(4′). Helv. Chim. Acta 91, 1533– 1552, DOI: 10.1002/hlca.200890167
  66
  Synthesis and evaluation of paromomycin derivatives modified at C(4')
  Pathak, Rashmi; Perez-Fernandez, Deborah; Nandurdikar, Rahul; Kalapala, Sarath K.; Bottger, Erik C.; Vasella, Andrea
  Helvetica Chimica Acta (2008), 91 (8), 1533-1552CODEN: HCACAV; ISSN:0018-019X. (Verlag Helvetica Chimica Acta)
  The 2-amino-2-deoxy-α-D-glucopyranosyl moiety (ring I) of paromomycin was replaced by a 2,4-diamino-2,4-dideoxy-α-D-glucopyranosyl, 2,4-diamino-2,4-dideoxy-α-D-galactopyranosyl, 2-amino-2-deoxy-α-D-galactopyranosyl, or 3,4,5-trideoxy-4-aza-α-D-erythro-heptoseptanosyl moiety to investigate the effect of the substituent at C(4') on the interaction with rRNA. Thus, title oligosaccharide I was prepd. from paromomycin via azidolysis, Dess-Martin's oxidn., stereoselective redn., periodate bond cleavage, azide redn., and debenzylation reactions. The derivs. possessing a D-galacto-configured ring I, e.g. I ( R = NH2, OH, R1 = H), were less active than the corresponding D-gluco-analogs and paromomycin. The C(4')-aminodeoxy deriv. I (R = H, R1 = NH2) (D-gluco ring I) and the known 4'-deoxyparomomycin, prepd. by a new route, displayed slightly lower antibacterial activities than paromomycin. Cell-wall permeability is not responsible for the unexpectedly low activity for oligosaccharide I (R = H, R1 = NH2), as shown by cell-free translation assays. The results evidence that the orientation of the substituent at C(4') is more important than its nature for drug binding and activity.
67. 67
  Schmitz, J., Li, T., Bartz, U., and Gütschow, M. (2016) Cathepsin B Inhibitors: Combining Dipeptide Nitriles with an Occluding Loop Recognition Element by Click Chemistry. ACS Med. Chem. Lett. 7, 211– 216, DOI: 10.1021/acsmedchemlett.5b00474
  67
  Cathepsin B Inhibitors: Combining Dipeptide Nitriles with an Occluding Loop Recognition Element by Click Chemistry
  Schmitz, Janina; Li, Tianwei; Bartz, Ulrike; Guetschow, Michael
  ACS Medicinal Chemistry Letters (2016), 7 (3), 211-216CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
  An active site mapping of human cathepsin B with dipeptide nitrile inhibitors was performed for a combinatorial approach by introducing several points of diversity and stepwise optimizing the inhibitor structure. To address the occluding loop of cathepsin B by a carboxylate moiety, click chem. to generate linker-connected mols. was applied. Inhibitor (S,S)-N-(4-phenylbenzoyl)-3-bromophenylalanyl-O-((1-(carboxymethyl)-1H-1,2,3-triazol-4-yl)methyl)serine nitrile (compd. 17) exhibited Ki values of 41.3 nM, 27.3 nM, or 19.2 nM, depending on the substrate and pH of the assay. Kinetic data were discussed with respect to the conformational selection and induced fit models.
68. 68
  LaPlanche, L. A. and Rogers, M. T. (1964) cis and trans Configurations of the Peptide Bond in N-Monosubstituted Amides by Nuclear Magnetic Resonance. J. Am. Chem. Soc. 86, 337– 341, DOI: 10.1021/ja01057a007
  68
  Cis and trans configurations of the peptide bond in N-monosubstituted amides by nuclear magnetic resonance
  LaPlanche, Laurine A.; Rogers, Max T.
  Journal of the American Chemical Society (1964), 86 (3), 337-41CODEN: JACSAT; ISSN:0002-7863.
  The nuclear magnetic resonance spectra of 13 N-monosubstituted aliphatic amides show that N-methylformamide, N-ethylformamide, N-isopropylformamide, and N-tert-butylformamide exist in both the cis and the trans configuration about the central C.sbd.N bond. Although the trans form predominates, the % cis isomer increases as the N substituent becomes more bulky. Studies of the change in chem. shift of the N substituent on diln. with benzene are in accord with the peak assignments. Spin coupling consts. between the protons on C and N may be found for each isomer in H2SO4 solns. of the formamides. The remaining 9 amides, where the carbonyl substituent was larger than H, showed the presence of only the trans configuration.
69. 69
  Fowler, P., Bernet, B., and Vasella, A. (1996) A ¹H-NMR Spectroscopic Investigation of the Conformation of the Acetamido Group in Some Derivatives of N-Acetyl-D-allosamine and D-Glucosamine. Helv. Chim. Acta 79, 269– 287, DOI: 10.1002/hlca.19960790127
  69
  A 1H-NMR spectroscopic investigation of the conformation of the acetamide group in some derivatives of N-acetyl-D-allosamine and -D-glucosamine
  Fowler, Paul; Bernet, Bruno; Vasella, Andrea
  Helvetica Chimica Acta (1996), 79 (1), 269-87CODEN: HCACAV; ISSN:0018-019X. (Verlag Helvetica Chimica Acta)
  The population of the conformations obtained by rotation around the C(2)-N and the N-C(O) bonds of AllNAc, GlcNAc, and GlcNMeAc derivs. was investigated by 1H-NMR spectroscopy. The AllNAc-derived α-D- and β-D-pyranosides I [R or R1 = OMe, OCHMe2, OCH(CF3)2, OC6H4NO2], the AllNAc diazirine I (RR1 = N:N), and the GlcNAc-derived axial anomers II [R = OMe, OCH(CF3)2, OC6H4NO2; R1 = R3 = H; R2 = PhCH2] prefer the (Z)-anti-conformation. A significant population of the (Z)-syn-conformer in the (Z)-syn/(Z)-anti-equil. for the equatorial anomers and the GlcNAc diazirine II (RR1 = N:N; R2 = PhCH2; R3 = H; III) was evidenced by an upfield shift of H-C(2), downfield shifts of H-C(1) and H-C(3), and by NOE measurements. The population of the (Z)-syn-conformation depends on the substituent at C(1) and is highest for the hexafluoroisopropyl glycoside. The population of the (Z)-syn conformation depends on the substituent at C(1) and H-C(3), and by NOE measurements. The population of the (Z)-syn-conformation depends on the substituent at C(1) and is highest for the hexafluoroisopropyl glycoside. The population of the (Z)-syn-conformation of β-D-II (R = OMe; R1 = R3 = H; R2 = Me) decreases with increasing polarity of the solvent, but a substantial population is still obsd. for solns. in D2O. Whereas the α-D-anomers II (R = R2 = R3 = H; R1 = OMe or H) prefer the (Z)-anti-conformation in D2O soln., the corresponding β-D-anomers are mixts. of the (Z)-anti- and (Z)-sym-conformers. The diazirine III self-assocs. in CD2Cl2 soln. at concns. >0.005 M at low temps. The axial anomers II (R = H; R1 = OMe; R2 = H, Me, PhCH2; R3 = Me) are 2:1 to 3:1 mixts. of (Z)-anti- and (E)-anti-conformers whereas the corresponding β-D-glycosides are ca. 1:3:6 mixts. of (Z)-syn-, (Z)-anti-, and (E)-anti-conformers.
70. 70
  Hu, X., Zhang, W., Carmichael, I., and Serianni, A. S. (2010) Amide Cis-Trans Isomerization in Aqueous Solutions of Methyl N-Formyl-D-glucosaminides and Methyl N-Acetyl-D-glucosaminides: Chemical Equilibria and Exchange Kinetics. J. Am. Chem. Soc. 132, 4641– 4652, DOI: 10.1021/ja9086787
  70
  Amide Cis-Trans Isomerization in Aqueous Solutions of Methyl N-Formyl-D-glucosaminides and Methyl N-Acetyl-D-glucosaminides: Chemical Equilibria and Exchange Kinetics
  Hu, Xiaosong; Zhang, Wenhui; Carmichael, Ian; Serianni, Anthony S.
  Journal of the American Chemical Society (2010), 132 (13), 4641-4652CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  Amide cis-trans isomerization (CTI) in Me 2-deoxy-2-acylamido-D-glucopyranosides was investigated by 1H and 13C NMR spectroscopy. Singly 13C-labeled Me 2-deoxy-2-formamido-D-glucopyranoside (MeGlcNFm) anomers provided std. 1H and 13C chem. shifts and 1H-1H and 13C-13C spin-coupling consts. for cis and trans amides that are detected readily in aq. soln. Equipped with this information, doubly 13C-labeled Me 2-deoxy-2-acetamido-D-glucopyranoside (MeGlcNAc) anomers were investigated, leading to the detection and quantification of cis and trans amides in this biol. important aminosugar. In comparison to MeGlcNFm anomers, the percentage of cis amide in aq. solns. of MeGlcNAc anomers is small (∼23% for MeGlcNFm vs. ∼1.8% for MeGlcNAc at 42 °C) but nevertheless observable with assistance from 13C-labeling. Temp. studies gave thermodn. parameters ΔG°, ΔH°, and ΔS° for cis-trans interconversion in MeGlcNFm and MeGlcNAc anomers. Cis/trans equil. depended on anomeric configuration, with solns. of α-anomers contg. less cis amide than those of β-anomers. Confirmation of the presence of cis amide in MeGlcNAc solns. derived from quant. 13C satn. transfer measurements of CTI rate consts. as a function of soln. temp., yielding activation parameters Eact, ΔG°⧧, ΔH°⧧, and ΔS°⧧ for saccharide CTI. Rate consts. for the conversion of trans to cis amide in MeGlcNFm and MeGlcNAc anomers ranged from 0.02 to 3.59 s-1 over 31-85 °C, compared to 0.24-80 s-1 for the conversion of cis to trans amide over the same temp. range. Energies of activation ranged from 16-19 and 19-20 kcal/mol for the cis → trans and trans → cis processes, resp. Complementary DFT calcns. on MeGlcNFm and MeGlcNAc model structures were conducted to evaluate the effects of an acyl side chain and anomeric structure, as well as C2-N2 bond rotation, on CTI energetics. These studies show that aq. solns. of GlcNAc-contg. structures contain measurable amts. of both cis and trans amides, which may influence their biol. properties.
71. 71
  Naito, T., Nakagawa, S., Narita, Y., and Kawaguchi, H. (1976) Chemical Modification of Sorbistin. N-Acyl Analogs of Sorbistin. J. Antibiot. 29, 1286– 1296, DOI: 10.7164/antibiotics.29.1286
  71
  Chemical modification of sorbistin. I. N-acyl analogs of sorbistin
  Naito, Takayuki; Nakagawa, Susumu; Narita, Yukio; Kawaguchi, Hiroshi
  Journal of Antibiotics (1976), 29 (12), 1286-96CODEN: JANTAJ; ISSN:0021-8820.
  Sorbistin A1 I (R = COEt) (II) and sorbistin B1 I (R = COMe) produced by Pseudomonas were converted into III by blocking the 1- and 4-amino groups with dimedone and subsequent deacylation of the 4'-N-acyl group. 4'-N-acyl analogs of sorbistin were prepd. by 4'-N-acylation of III by the mixed anhydride, acid chloride, or activated ester methods, followed by deblocking with Br2 or NaNO2. Sorbistins I (R = COMe, COPr) and II were interconverted by this method. Acyl derivs. of sorbistin D I (R = H), were prepd. In vitro antimicrobial activity showed that I (R = cyclopropylcarbonyl) and II were most active. Elongation and shortening of the side chain and introduction of functional groups decreased the activity. N-acylation of the N-1 or N-4 amino groups gave inactive products.
72. 72
  Hanessian, S., Takamoto, T., and Masse, R. (1975) Oxidative Degradations Leading to Novel Biochemical Probes and Synthetic Intermediates. J. Antibiot. 28, 835– 836, DOI: 10.7164/antibiotics.28.835
  72
  Aminoglycoside antibiotics. Oxidative degradations leading to novel biochemical probes and synthetic intermediates
  Hanessian, Stephen; Takamoto, Tetsuyoshi; Masse, Robert
  Journal of Antibiotics (1975), 28 (10), 835-7CODEN: JANTAJ; ISSN:0021-8820.
  I [R = H (II), 2,6-diamino-2,6-dideoxy-α-D-glucopyranosyl (III)] were prepd. by sequential HIO4 oxidn. and β-eliminative degrdn. of paromomycin and neomycin B, resp. II was devoid of antibacterial activity whereas III had 4-10 times less activity than neamine.
73. 73
  Pathak, R., Böttger, E. C., and Vasella, A. (2005) Design and Synthesis of Aminoglycoside Antibiotics to Selectively Target 16S Ribosomal RNA Position 1408. Helv. Chim. Acta 88, 2967– 2984, DOI: 10.1002/hlca.200590240
  73
  Design and synthesis of amino glycoside antibiotics to selectively target 16S ribosomal RNA position 1408
  Pathak, Rashmi; Bottger, Erik C.; Vasella, Andrea
  Helvetica Chimica Acta (2005), 88 (11), 2967-2985CODEN: HCACAV; ISSN:0018-019X. (Verlag Helvetica Chimica Acta)
  The glucopyranosyl moiety (ring I) of paromomycin was modified in a search for novel amino-glycoside antibiotics, e.g. I•5CF3COOH, via regioselective fluoro-dehydroxylation and reductive fragmentation reactions. As compared to paromomycin, the C(6')-deoxy and fluoro-deoxy derivs., e.g. I•5CF3COOH, showed a lower activity against both wild type 1408A and 1408G mutant ribosomes.
74. 74
  Fukami, H., Ikeda, S., Kitahara, K., and Nakajima, M. (1977) Total Synthesis of Ribostamycin. Agric. Biol. Chem. 41, 1689– 1694, DOI: 10.1271/bbb1961.41.1689
  74
  Synthetic studies on carbohydrate antibiotics. XVIII. Total synthesis of ribostamycin
  Fukami, Harukazu; Ikeda, Shoji; Kitahara, Katsuhiko; Nakajima, Minoru
  Agricultural and Biological Chemistry (1977), 41 (9), 1689-94CODEN: ABCHA6; ISSN:0002-1369.
  Suitably protected 5-O-β-D-ribofuranosyl-2-deoxystreptamine was condensed with protected 2,6-diamino-2,6-dideoxy-α-D-glucopyranosyl bromide by a modified Koenigs-Knorr reaction to give 3 condensation products, one of which was confirmed as a ribostamycin deriv. The others were designated as its 6-O-α- and 6-O-β-isomers by the PMR spectra of their free bases and N-acetyl derivs. and by their chem. reactions.
75. 75
  Carter, A. P., Clemons, W. M., Brodersen, D. E., Morgan-Warren, R. J., Wimberly, B. T., and Ramakrishnan, V. (2000) Functional Insights from the Structure of the 30S Ribosomal Subunit and its Interactions with Antibiotics. Nature 407, 340– 348, DOI: 10.1038/35030019
  75
  Functional insights from the structure of the 30S ribosomal subunit and its interactions with antibiotics
  Carter, Andrew P.; Clemons, William M.; Brodersen, Ditlev E.; Morgan-Warren, Robert J.; Wimberly, Brian T.; Ramakrishnan, V.
  Nature (London) (2000), 407 (6802), 340-348CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
  The 30S ribosomal subunit has two primary functions in protein synthesis. It discriminates against aminoacyl tRNAs that do not match the codon of mRNA, thereby ensuring accuracy in translation of the genetic message in a process called decoding. Also, it works with the 50S subunit to move the tRNAs and assocd. mRNA by precisely one codon, in a process called translocation. Here we describe the functional implications of the high-resoln. 30S crystal structure presented in the accompanying paper, and infer details of the interactions between the 30S subunit and its tRNA and mRNA ligands. We also describe the crystal structure of the 30S subunit complexed with the antibiotics paromomycin, streptomycin and spectinomycin, which interfere with decoding and translocation. This work reveals the structural basis for the action of these antibiotics, and leads to a model for the role of the universally conserved 16S RNA residues A1492 and A1493 in the decoding process.
76. 76
  Hobbie, S. N., Kalapala, S. K., Akshay, S., Bruell, C., Schmidt, S., Dabow, S., Vasella, A., Sander, P., and Böttger, E. C. (2007) Engineering the rRNA Decoding Site of Eukaryotic Cytosolic Ribosomes in Bacteria. Nucleic Acids Res. 35, 6086– 6093, DOI: 10.1093/nar/gkm658
  76
  Engineering the rRNA decoding site of eukaryotic cytosolic ribosomes in bacteria
  Hobbie, Sven N.; Kalapala, Sarath K.; Akshay, Subramanian; Bruell, Christian; Schmidt, Sebastian; Dabow, Sabine; Vasella, Andrea; Sander, Peter; Boettger, Erik C.
  Nucleic Acids Research (2007), 35 (18), 6086-6093CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
  Structural and genetic studies on prokaryotic ribosomes have provided important insights into fundamental aspects of protein synthesis and translational control and its interaction with ribosomal drugs. Comparable mechanistic studies in eukaryotes are mainly hampered by the absence of both high-resoln. crystal structures and efficient genetic models. To study the interaction of aminoglycoside antibiotics with selected eukaryotic ribosomes, we replaced the bacterial drug binding site in 16S rRNA with its eukaryotic counterpart, resulting in bacterial hybrid ribosomes with a fully functional eukaryotic rRNA decoding site. Cell-free translation assays demonstrated that hybrid ribosomes carrying the rRNA decoding site of higher eukaryotes show pronounced resistance to aminoglycoside antibiotics, equiv. to that of rabbit reticulocyte ribosomes, while the decoding sites of parasitic protozoa show distinctive drug susceptibility. Our findings suggest that phylogenetically variable components of the ribosome, other than the rRNA-binding site, do not affect aminoglycoside susceptibility of the protein-synthesis machinery. The activities of the hybrid ribosomes indicate that helix 44 of the rRNA decoding site behaves as an autonomous domain, which can be exchanged between ribosomes of different phylogenetic domains for study of function.
77. 77
  Hobbie, S. N., Akshay, S., Kalapala, S. K., Bruell, C., Shcherbakov, D., and Böttger, E. C. (2008) Genetic Analysis of Interactions with Eukaryotic rRNA Identify the Mitoribosome as Target in Aminoglycoside Ototoxicity. Proc. Natl. Acad. Sci. U. S. A. 105, 20888– 20893, DOI: 10.1073/pnas.0811258106
  77
  Genetic analysis of interactions with eukaryotic rRNA identify the mitoribosome as target in aminoglycoside ototoxicity
  Hobbie, Sven N.; Akshay, Subramanian; Kalapala, Sarath K.; Bruell, Christian M.; Shcherbakov, Dmitry; Bottger, Eric C.
  Proceedings of the National Academy of Sciences of the United States of America (2008), 105 (52), 20888-20893CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
  Aminoglycoside ototoxicity has been related to a surprisingly large no. of cellular structures and metabolic pathways. The finding that patients with mutations in mitochondrial rRNA are hypersusceptible to aminoglycoside-induced hearing loss has indicated a possible role for mitochondrial protein synthesis. To study the mol. interaction of aminoglycosides with eukaryotic ribosomes, we made use of the observation that the drug binding site is a distinct domain defined by the small subunit rRNA, and investigated drug susceptibility of bacterial hybrid ribosomes carrying various alleles of the eukaryotic decoding site. Compared to hybrid ribosomes with the A site of human cytosolic ribosomes, susceptibility of mitochondrial hybrid ribosomes to various aminoglycosides correlated with the relative cochleotoxicity of these drugs. Sequence alterations that correspond to the mitochondrial deafness mutations A1555G and C1494T increased drug-binding and rendered the ribosomal decoding site hypersusceptible to aminoglycoside-induced mistranslation and inhibition of protein synthesis. Our results provide exptl. support for aminoglycoside-induced dysfunction of the mitochondrial ribosome. We propose a pathogenic mechanism in which interference of aminoglycosides with mitochondrial protein synthesis exacerbates the drugs' cochlear toxicity, playing a key role in sporadic dose-dependent and genetically inherited, aminoglycoside-induced deafness.
78. 78
  Hobbie, S. N., Bruell, C. M., Akshay, S., Kalapala, S. K., Shcherbakov, D., and Böttger, E. C. (2008) Mitochondrial Deafness Alleles Confer Misreading of the Genetic Code. Proc. Natl. Acad. Sci. U. S. A. 105, 3244– 3249, DOI: 10.1073/pnas.0707265105
  78
  Mitochondrial deafness alleles confer misreading of the genetic code
  Hobbie, Sven N.; Bruell, Christian M.; Akshay, Subramanian; Kalapala, Sarath K.; Shcherbakov, Dmitry; Bottger, Erik C.
  Proceedings of the National Academy of Sciences of the United States of America (2008), 105 (9), 3244-3249CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
  Despite the fact that important genetic diseases are caused by mutant mitochondrial ribosomes, the mol. mechanisms by which such ribosomes result in a clin. phenotype remain largely unknown. The absence of exptl. models for mitochondrial diseases has also prevented the rational search for therapeutic interventions. Here, we report on the construction of bacterial hybrid ribosomes that contain various versions of the mitochondrial decoding region of rRNA. We show that the pathogenic mutations A1555G and C1494T decrease the accuracy of translation and render the ribosomal decoding site hypersusceptible to aminoglycoside antibiotics. This finding suggests misreading of the genetic code as an important mol. mechanism in disease pathogenesis.
79. 79
  Hobbie, S. N., Kaiser, M., Schmidt, S., Shcherbakov, D., Janusic, T., Brun, R., and Böttger, E. C. (2011) Genetic Reconstruction of Protozoan rRNA Decoding Sites Provides a Rationale for Paromomycin Activity against Leishmania and Trypanosoma. PLoS Neglected Trop. Dis. 5, e1161 DOI: 10.1371/journal.pntd.0001161
  79
  Genetic reconstruction of protozoan rRNA decoding sites provides a rationale for paromomycin activity against Leishmania and Trypanosoma
  Hobbie, Sven N.; Kaiser, Marcel; Schmidt, Sebastian; Shcherbakov, Dmitri; Janusic, Tanja; Brun, Reto; Bottger, Erik C.
  PLoS Neglected Tropical Diseases (2011), 5 (5), e1161CODEN: PNTDAM; ISSN:1935-2735. (Public Library of Science)
  Aminoglycoside antibiotics target the ribosomal decoding A-site and are active against a broad spectrum of bacteria. These compds. bind to a highly conserved stem-loop-stem structure in helix 44 of bacterial 16S rRNA. One particular aminoglycoside, paromomycin, also shows potent antiprotozoal activity and is used for the treatment of parasitic infections, e.g. by Leishmania spp. The precise drug target is, however, unclear; in particular whether aminoglycoside antibiotics target the cytosolic and/or the mitochondrial protozoan ribosome. To establish an exptl. model for the study of protozoan decoding-site function, we constructed bacterial chimeric ribosomes where the central part of bacterial 16S rRNA helix 44 has been replaced by the corresponding Leishmania and Trypanosoma rRNA sequences. Relating the results from in vitro ribosomal assays to that of in vivo aminoglycoside activity against Trypanosoma brucei, as assessed in cell cultures and in a mouse model of infection, we conclude that aminoglycosides affect cytosolic translation while the mitochondrial ribosome of trypanosomes is not a target for aminoglycoside antibiotics.
80. 80
  Qian, Y. and Guan, M.-X. (2009) Interaction of Aminoglycosides with Human Mitochondrial 12S rRNA Carrying the Deafness-Associated Mutation. Antimicrob. Agents Chemother. 53, 4612– 4618, DOI: 10.1128/AAC.00965-08
  80
  Interaction of aminoglycosides with human mitochondrial 12S rRNA carrying the deafness-associated mutation
  Qian, Yaping; Guan, Min-Xin
  Antimicrobial Agents and Chemotherapy (2009), 53 (11), 4612-4618CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
  The mitochondrial 12S rRNA A1555G mutation is one of the important causes of aminoglycoside-induced and nonsyndromic hearing loss. Here the authors employed an RNA-directed chem.-modification approach to understanding the pathogenesis of aminoglycoside-induced hearing loss. The patterns of chem. modification of RNA oligonucleotides carrying the A1555G mutation by di-Me sulfate (DMS) were distinct from those of the RNA oligonucleotides carrying wild-type sequence in the presence of aminoglycosides. In the RNA analog carrying the A1555G mutation, reduced reactivity to DMS occurred in base G1555 as well as in bases C1556 and A1553 in the presence of paromomycin, neomycin, gentamicin, kanamycin, tobramycin, or streptomycin. In particular, base G1555 exhibited marked but similar levels of protection in the presence of 0.1 μM to 100 μM neomycin, gentamicin, or kanamycin. In contrast, the levels of protection in base G1555 appeared to be correlated with the concn. of paromycin, tobramycin, or streptomycin. Furthermore, increasing reactivities to DMS in the presence of these aminoglycosides were obsd. for bases A1492, C1493, C1494, and A1557 in the RNA analog carrying the A1555G mutation. These data suggested that the A1555G mutation altered the binding properties of aminoglycosides at the A site of 12S rRNA and led to local conformational changes in 12S rRNA carrying the A1555G mutation. The interaction between aminoglycosides and 12S rRNA carrying the A1555G mutation provides new insight into the pathogenesis of aminoglycoside ototoxicity.
81. 81
  Prezant, T. R., Agapian, J. V., Bohlman, M. C., Bu, X., Öztas, S., Qiu, W.-Q., Arnos, K. S., Cortopassi, G. A., Jaber, L., Rotter, J. I., Shohat, M., and Fischel-Ghodsian, N. (1993) Mitochondrial Ribosomal RNA Mutation Associated with Both Antibiotic-Induced and Non-Syndromic Deafness. Nat. Genet. 4, 289– 294, DOI: 10.1038/ng0793-289
  81
  Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness
  Prezant, Toni R.; Agapian, John V.; Bohlman, M. Charlotte; Bu, Xiangdong; Oztas, Sitki; Qiu, Wei Qin; Arnos, Kathleen S.; Cortopassi, Gino A.; Jaber, Lutfi; et al.
  Nature Genetics (1993), 4 (3), 289-94CODEN: NGENEC; ISSN:1061-4036.
  Maternally transmitted non-syndromic deafness was described recently both in pedigrees with susceptibility to aminoglycoside ototoxicity and in a large Arab-Israeli pedigree. Because of the known action of aminoglycosides on bacterial ribosomes, the authors analyzed the sequence of mitochondrial rRNA genes of three unrelated patients with familial aminoglycoside-induced deafness. The authors also sequenced the complete mitochondrial genome of the Arab-Israeli pedigree. All four families shared a nucleotide 1555 A to G substitution in the 12S rRNA gene, a site implicated in aminoglycoside activity. This study offers the first description of a mitochondrial rRNA mutation leading to disease, the first cases of non-syndromic deafness caused by a mitochondrial DNA mutation and the first mol. genetic study of antibiotic-induced ototoxicity.
82. 82
  Tadanier, J., Martin, J. R., Johnson, P., Goldstein, A. W., and Hallas, R. (1980) 2′-N-Acylfortimicins and 2′-N-Alkylfortimicins via the Isofortimicin Rearrangement. Carbohydr. Res. 85, 61– 71, DOI: 10.1016/S0008-6215(00)84564-4
  82
  2'-N-Acylfortimicins and 2'-N-alkylfortimicins via the isofortimicin rearrangement
  Tadanier, Jack; Martin, Jerry R.; Johnson, Paulette; Goldstein, Alma W.; Hallas, Robert
  Carbohydrate Research (1980), 85 (1), 61-71CODEN: CRBRAT; ISSN:0008-6215.
  Fortimicin A and a no. of 4-N-acylfortimicins B, although stable as either the fully protonated hydrochloride or sulfate salts, undergo degrdn. as the free bases in aq. soln. Detailed studies with fortimicin A and 4-N-acetylfortimicin B show that degrdn. occurs, in part, by simple cleavage of the 4-N-acyl groups with formation of fortimicin B, and, in part, by rearrangement to the 2'-N-acylfortimicins B (the isofortimicin rearrangement). The conversions of the rearrangement products into 2'-N-glycylfortimicin A, 2'-N-acetylfortimicin A, and the 2'-N-(2-aminoethyl)fortimicins A and B are described. The antibacterial activities of the new fortimicin A derivs. were less than that of fortimicin A.
83. 83
  Satoi, S., Awata, M., Muto, N., Hayashi, M., Sagai, H., and Otani, M. (1983) A New Aminoglycoside Antibiotic G-367 S₁, 2′-N-Formylsisomicin. Fermentation, Isolation and Characterization. J. Antibiot. 36, 1– 5, DOI: 10.7164/antibiotics.36.1
  83
  A new aminoglycoside antibiotic G-367 S1, 2'-N-formylsisomicin. Fermentation, isolation and characterization
  Satoi, Shuzo; Awata, Masashi; Muto, Naoki; Hayashi, Mitsuo; Sagai, Hitoshi; Otani, Masaru
  Journal of Antibiotics (1983), 36 (1), 1-5CODEN: JANTAJ; ISSN:0021-8820.
  A new aminoglycoside antibiotic, G-367 S1 (I) produced by a rare actinomycete, Dactylosporangium thailandense G-367 (FERM-P 4840) was isolated by column chromatog. on a cation-exchange resin. G-367 S1 is active against gram-pos. and gram-neg. bacteria.
84. 84
  Wong, C.-H., Hendrix, M., Manning, D. D., Rosenbohm, C., and Greenberg, A. A. (1998) A Library Approach to the Discovery of Small Molecules That Recognize RNA: Use of a 1,3-Hydroxyamine Motif as Core. J. Am. Chem. Soc. 120, 8319– 8327, DOI: 10.1021/ja980826p
  84
  A Library Approach to the Discovery of Small Molecules That Recognize RNA: Use of a 1,3-Hydroxyamine Motif as Core
  Wong, Chi-Huey; Hendrix, Martin; Manning, David D.; Rosenbohm, Christoph; Greenberg, William A.
  Journal of the American Chemical Society (1998), 120 (33), 8319-8327CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  A library of compds. based upon an amino-glucopyranoside core has been developed and screened for binding to RNA and specifically to 16S rRNA. The title mols. simplify the complexity of naturally occurring aminoglycoside antibiotics by embodying a putative recognition motif found within these structures, namely, a 1,3-hydroxyamine. The core pyranoside bearing the hydroxyamine motif was structurally varied at two points through a combinatorial approach utilizing acylation and reductive amination protocols. The aminoglycoside mimetics were screened in an automated assay based upon surface plasmon resonance (SPR), and some were found effective at binding a 27-nucleotide model (AS-wt) of A-site 16S RNA as well as a drug-resistant mutant RNA in the micro-molar range.
85. 85
  Nessar, R., Cambau, E., Reyrat, J. M., Murray, A., and Gicquel, B. (2012) Mycobacterium abscessus: A New Antibiotic Nightmare. J. Antimicrob. Chemother. 67, 810– 818, DOI: 10.1093/jac/dkr578
  85
  Mycobacterium abscessus: A new antibiotic nightmare
  Nessar, Rachid; Cambau, Emmanuelle; Reyrat, Jean Marc; Murray, Alan; Gicquel, Brigitte
  Journal of Antimicrobial Chemotherapy (2012), 67 (4), 810-818CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
  A review. The intrinsic and acquired resistance of Mycobacterium abscessus to commonly used antibiotics limits the chemotherapeutic options for infections caused by these mycobacteria. Intrinsic resistance is attributed to a combination of the permeability barrier of the complex multilayer cell envelope, drug export systems, antibiotic targets with low affinity and enzymes that neutralize antibiotics in the cytoplasm. To date, acquired resistance has only been obsd. for aminoglycosides and macrolides, which is conferred by mutations affecting the genes encoding the antibiotic targets (rrs and rrl, resp.). Here, the authors summarize previous and recent findings on the resistance of M. abscessus to antibiotics in light of what has been discovered for other mycobacteria. Since we can now distinguish three groups of strains belonging to M. abscessus (M. abscessus sensu stricto, Mycobacterium massiliense and Mycobacterium bolletii), studies on antibiotic susceptibility and resistance should be considered according to this new classification. This review raises the profile of this important pathogen and highlights the work needed to decipher the mol. events responsible for its extensive chemotherapeutic resistance.
86. 86
  Maurer, F. P., Bruderer, V. L., Castelberg, C., Ritter, C., Scherbakov, D., Bloemberg, G. V., and Böttger, E. C. (2015) Aminoglycoside-modifying Enzymes Determine the Innate Susceptibility to Aminoglycoside Antibiotics in Rapidly Growing Mycobacteria. J. Antimicrob. Chemother. 70, 1412– 1419, DOI: 10.1093/jac/dku550
  86
  Aminoglycoside-modifying enzymes determine the innate susceptibility to aminoglycoside antibiotics in rapidly growing mycobacteria
  Maurer, Florian P.; Bruderer, Vera L.; Castelberg, Claudio; Ritter, Claudia; Scherbakov, Dimitri; Bloemberg, Guido V.; Bottger, Erik C.
  Journal of Antimicrobial Chemotherapy (2015), 70 (5), 1412-1419CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
  Infections caused by the rapidly growing mycobacterium (RGM) Mycobacterium abscessus are notoriously difficult to treat due to the innate resistance of M. abscessus to most clin. available antimicrobials. Aminoglycoside antibiotics (AGA) are a cornerstone of antimicrobial chemotherapy against M. abscessus infections, although little is known about intrinsic drug resistance mechanisms. The authors investigated the role of chromosomally encoded putative aminoglycoside-modifying enzymes (AME) in AGA susceptibility in M. abscessus. Clin. isolates of M. abscessus were tested for susceptibility to a series of AGA with different substituents at positions 2', 3' and 4' of ring 1 in MIC assays. Cell-free exts. of M. abscessus type strain ATCC 19977 and Mycobacterium smegmatis strains SZ380 [aac(2')-Id+], EP10 [aac(2')-Id-] and SZ461 [aac(2')-Id+, rrs A1408G] were investigated for AGA acetylation activity using thin-layer chromatog. (TLC). Cell-free ribosome translation assays were performed to directly study drug-target interaction. Cell-free translation assays demonstrated that ribosomes of M. abscessus and M. smegmatis show comparable susceptibility to all tested AGA. MIC assays for M. abscessus and M. smegmatis, however, consistently showed the lowest MIC values for 2'-hydroxy-AGA as compared with 2'-amino-AGA, indicating that an aminoglycoside-2'-acetyltransferase, Aac(2'), contributes to innate AGA susceptibility. TLC expts. confirmed enzymic activity consistent with Aac(2'). Using M. smegmatis as a model for RGM, acetyltransferase activity was shown to be up-regulated in response to AGA-induced inhibition of protein synthesis. The findings point to AME as important determinants of AGA susceptibility in M. abscessus.
87. 87
  François, B., Russell, R. J. M., Murray, J. B., Aboul-Ela, F., Masquid, B., Vicens, Q., and Westhof, E. (2005) Crystal Structures of Complexes Between Aminoglycosides and Decoding A Site Oligonucleotides: Role of the Number of Rings and Positive Charges in the Specific Binding Leading to Miscoding. Nucleic Acids Res. 33, 5677– 5690, DOI: 10.1093/nar/gki862
  87
  Crystal structures of complexes between aminoglycosides and decoding A site oligonucleotides: role of the number of rings and positive charges in the specific binding leading to miscoding
  Francois, Boris; Russell, Rupert J. M.; Murray, James B.; Aboul-ela, Fareed; Masquida, Benoit; Vicens, Quentin; Westhof, Eric
  Nucleic Acids Research (2005), 33 (17), 5677-5690CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
  The crystal structures of six complexes between aminoglycoside antibiotics (neamine, gentamicin C1A, kanamycin A, ribostamycin, lividomycin A and neomycin B) and oligonucleotides contg. the decoding A site of bacterial ribosomes are reported at resolns. between 2.2 and 3.0 Å. Although the no. of contacts between the RNA and the aminoglycosides varies between 20 and 31, up to eight direct hydrogen bonds between rings I and II of the neamine moiety are conserved in the obsd. complexes. The puckered sugar ring I is inserted into the A site helix by stacking against G1491 and forms a pseudo base pair with two H-bonds to the Watson-Crick sites of the universally conserved A1408. This central interaction helps to maintain A1492 and A1493 in a bulged-out conformation. All these structures of the minimal A site RNA complexed to various aminoglycosides display crystal packings with intermol. contacts between the bulging A1492 and A1493 and the shallow/minor groove of Watson-Crick pairs in a neighboring helix. In one crystal, one empty A site is obsd. In two crystals, two aminoglycosides are bound to the same A site with one bound specifically and the other bound in various ways in the deep/major groove at the edge of the A sites.
88. 88
  Kaul, M. and Pilch, D. S. (2002) Thermodynamics of Aminoglycoside-rRNA Recognition: The Binding of Neomycin-Class Aminoglycosides to the A Site of 16S rRNA. Biochemistry 41, 7695– 7706, DOI: 10.1021/bi020130f
  88
  Thermodynamics of Aminoglycoside-rRNA Recognition: The Binding of Neomycin-Class Aminoglycosides to the A Site of 16S rRNA
  Kaul, Malvika; Pilch, Daniel S.
  Biochemistry (2002), 41 (24), 7695-7706CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
  We use spectroscopic and calorimetric techniques to characterize the binding of the aminoglycoside antibiotics neomycin, paromomycin, and ribostamycin to a RNA oligonucleotide that models the A-site of Escherichia coli 16S rRNA. Our results reveal the following significant features: (i) Aminoglycoside binding enhances the thermal stability of the A-site RNA duplex, with the extent of this thermal enhancement decreasing with increasing pH and/or Na+ concn. (ii) The RNA binding enthalpies of the aminoglycosides become more exothermic (favorable) with increasing pH, an observation consistent with binding-linked protonation of one or more drug amino groups. (iii) Isothermal titrn. calorimetry (ITC) studies conducted as a function of buffer reveal that aminoglycoside binding to the host RNA is linked to the uptake of protons, with the no. of linked protons being dependent on pH. Specifically, increasing the pH results in a corresponding increase in the no. of linked protons. (iv) ITC studies conducted at 25 and 37° reveal that aminoglycoside-RNA complexation is assocd. with a neg. heat capacity change (ΔCp), the magnitude of which becomes greater with increasing pH. (v) The obsd. RNA binding affinities of the aminoglycosides decrease with increasing pH and/or Na+ concn. In addn., the thermodn. forces underlying these RNA binding affinities also change as a function of pH. Specifically, with increasing pH, the enthalpic contribution to the obsd. RNA binding affinity increases, while the corresponding entropic contribution to binding decreases. (vi) The affinities of the aminoglycosides for the host RNA follow the hierarchy neomycin > paromomycin > ribostamycin. The enhanced affinity of neomycin relative to either paromomycin or ribostamycin is primarily, if not entirely, enthalpic in origin. (vii) The salt dependencies of the RNA binding affinities of neomycin and paromomycin are consistent with at least three drug NH3+ groups participating in electrostatic interactions with the host RNA. In the aggregate, our results reveal the impact of specific alterations in aminoglycoside structure on the thermodn. of binding to an A-site model RNA oligonucleotide. Such systematic comparative studies are crit. first steps toward establishing the thermodn. database required for enhancing our understanding of the mol. forces that dictate and control aminoglycoside recognition of RNA.
89. 89
  Kaul, M., Barbieri, C. M., Kerrigan, J. E., and Pilch, D. S. (2003) Coupling of Drug Protonation to the Specific Binding of Aminoglycosides to the A Site of 16 S rRNA: Elucidation of the Number of Drug Amino Groups Involved and their Identities. J. Mol. Biol. 326, 1373– 1387, DOI: 10.1016/S0022-2836(02)01452-3
  89
  Coupling of Drug Protonation to the Specific Binding of Aminoglycosides to the A Site of 16 S rRNA: Elucidation of the Number of Drug Amino Groups Involved and their Identities
  Kaul, Malvika; Barbieri, Christopher M.; Kerrigan, John E.; Pilch, Daniel S.
  Journal of Molecular Biology (2003), 326 (5), 1373-1387CODEN: JMOBAK; ISSN:0022-2836. (Elsevier Science Ltd.)
  2-Deoxystreptamine (2-DOS) aminoglycoside antibiotics bind specifically to the central region of the 16 S rRNA A site and interfere with protein synthesis. Recently, we have shown that the binding of 2-DOS aminoglycosides to an A site model RNA oligonucleotide is linked to the protonation of drug amino groups. Here, we extend these studies to define the no. of amino groups involved as well as their identities. Specifically, we use pH-dependent 15N NMR spectroscopy to det. the pKa values of the amino groups in neomycin B, paromomycin I, and lividomycin A sulfate, with the resulting pKa values ranging from 6.92 to 9.51. For each drug, the 3-amino group was assocd. with the lowest pKa, with this value being 6.92 in neomycin B, 7.07 in paromomycin I, and 7.24 in lividomycin A. In addn., we use buffer-dependent isothermal titrn. calorimetry (ITC) to det. the no. of protons linked to the complexation of the three drugs with the A site model RNA oligomer at pH 5.5, 8.8, or 9.0. At pH 5.5, the binding of the three drugs to the host RNA is independent of drug protonation effects. By contrast, at pH 9.0, the RNA binding of paromomycin I and neomycin B is coupled to the uptake of 3.25 and 3.80 protons, resp., with the RNA binding of lividomycin A at pH 8.8 being coupled to the uptake of 3.25 protons. A comparison of these values with the protonation states of the drugs predicted by our NMR-derived pKa values allows us to identify the specific drug amino groups whose protonation is linked to complexation with the host RNA. These detns. reveal that the binding of lividomycin A to the host RNA is coupled to the protonation of all five of its amino groups, with the RNA binding of paromomycin I and neomycin B being linked to the protonation of four and at least five amino groups, resp. For paromomycin I, the protonation reactions involve the 1-, 3-, 2'-, and 2'''-amino groups, while, for neomycin B, the binding-linked protonation reactions involve at least the 1-, 3-, 2', 6'-, and 2'''-amino groups. Our results clearly identify drug protonation reactions as important thermodn. participants in the specific binding of 2-DOS aminoglycosides to the A site of 16 S rRNA.
90. 90
  Wasserman, M. R., Pulk, A., Zhou, Z., Altman, R. B., Zinder, J. C., Green, K. D., Garneau-Tsodikova, S., Doudna Cate, J. H., and Blanchard, S. C. (2015) Chemically Related 4,5-Linked Aminoglycoside Antibiotics Drive Subunit Rotation in Opposite Directions. Nat. Commun. 6, 7896, DOI: 10.1038/ncomms8896
  90
  Chemically related 4,5-linked aminoglycoside antibiotics drive subunit rotation in opposite directions
  Wasserman, Michael R.; Pulk, Arto; Zhou, Zhou; Altman, Roger B.; Zinder, John C.; Green, Keith D.; Garneau-Tsodikova, Sylvie; Doudna Cate, Jamie H.; Blanchard, Scott C.
  Nature Communications (2015), 6 (), 7896CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)
  Dynamic remodelling of intersubunit bridge B2, a conserved RNA domain of the bacterial ribosome connecting helixes 44 (h44) and 69 (H69) of the small and large subunit, resp., impacts translation by controlling intersubunit rotation. Here we show that aminoglycosides chem. related to neomycin-paromomycin, ribostamycin and neamine-each bind to sites within h44 and H69 to perturb bridge B2 and affect subunit rotation. Neomycin and paromomycin, which only differ by their ring-I 6'-polar group, drive subunit rotation in opposite directions. This suggests that their distinct actions hinge on the 6'-substituent and the drug's net pos. charge. By solving the crystal structure of the paromomycin-ribosome complex, we observe specific contacts between the apical tip of H69 and the 6'-hydroxyl on paromomycin from within the drug's canonical h44-binding site. These results indicate that aminoglycoside actions must be framed in the context of bridge B2 and their regulation of subunit rotation.
91. 91
  Vacas, T., Corzana, F., Jiménez-Osés, G., González, C., Gómez, A. M., Bastida, A., Revuelta, J., and Asensio, J. L. (2010) Role of Aromatic Rings in the Molecular Recognition of Aminoglycoside Antibiotics: Implications for Drug Design. J. Am. Chem. Soc. 132, 12074– 12090, DOI: 10.1021/ja1046439
  91
  Role of Aromatic Rings in the Molecular Recognition of Aminoglycoside Antibiotics: Implications for Drug Design
  Vacas, Tatiana; Corzana, Francisco; Jimenez-Oses, Gonzalo; Gonzalez, Carlos; Gomez, Ana M.; Bastida, Agatha; Revuelta, Julia; Asensio, Juan Luis
  Journal of the American Chemical Society (2010), 132 (34), 12074-12090CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  Aminoglycoside antibiotics participate in a large variety of binding processes involving both RNA and proteins. The description, in recent years, of several clin. relevant aminoglycoside/receptor complexes has greatly stimulated the structural-based design of new bioactive derivs. Unfortunately, design efforts have frequently met with limited success, reflecting our incomplete understanding of the mol. determinants for the antibiotic recognition. Intriguingly, arom. rings of the protein/RNA receptors seem to be key actors in this process. Indeed, close inspection of the structural information available reveals that they are frequently involved in CH/π stacking interactions with sugar/amino-cyclitol rings of the antibiotic. While the interaction between neutral carbohydrates and arom. rings has been studied in detail during past decade, little is known about these contacts when they involve densely charged glycosides. Herein we report a detailed exptl. and theor. anal. of the role played by CH/π stacking interactions in the mol. recognition of amino-glycosides. Our study aims to det. the influence that the antibiotic poly-cationic character has on the stability, preferred geometry, and dynamics of these particular contacts. With this purpose, different aminoglycoside/arom. complexes have been selected as model systems. They varied from simple bimol. interactions to the more stable intramol. CH/π contacts present in designed derivs. The obtained results highlight the key role played by electrostatic forces and the de-solvation of charged groups in the mol. recognition of poly-cationic glycosides and have clear implications for the design of improved antibiotics.
92. 92
  Hanessian, S., Saavedra, O. M., Vilchis-Reyes, M. A., Maianti, J. P., Kanazawa, H., Dozzo, P., Matias, R. D., Serio, A., and Kondo, J. (2014) Synthesis, Broad Spectrum Antibacterial Activity, and X-ray Co-crystal Structure of the Decoding Bacterial Ribosomal A-Site with 4′-Deoxy-4′-Fluoro Neomycin Analogs. Chem. Sci. 5, 4621– 4632, DOI: 10.1039/C4SC01626B
  92
  Synthesis, broad spectrum antibacterial activity, and X-ray co-crystal structure of the decoding bacterial ribosomal A-site with 4'-deoxy-4'-fluoro neomycin analogs
  Hanessian, S.; Saavedra, O. M.; Vilchis-Reyes, M. A.; Maianti, J. P.; Kanazawa, H.; Dozzo, P.; Matias, R. D.; Serio, A.; Kondo, J.
  Chemical Science (2014), 5 (12), 4621-4632CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
  This study reports the synthesis, antibacterial evaluation and nature of fluorine-rRNA contacts revealed by an X-ray co-crystal structure of a series of 4'-deoxy-4'-fluoro B-neomycin analogs. 4'-Deoxyfluorination improves the inhibition profile towards resistant enzymes and renders equally potent antibiotics compared to the parent neomycin B. The 4'-deoxy-4'-fluoro-4'-epi neomycin analogs showed a preferential inhibition over the 4'-deoxy-4'-fluoro neomycin counterpart against the strains of P. aeruginosa carrying a chromosomal APH(3')-IIb enzyme, known to inactivate the parent aminoglycoside. To the best of our knowledge, this is the first example of a neighboring-group aminoglycoside-modifying enzyme evasion by fluorine substitution. A unique F-G1491 stacking was obsd. in a co-crystal structure of 4'-deoxy-4'-fluoro-4'-epi neomycin with a bacterial rRNA A-site.
93. 93
  Hermann, T. and Westhof, E. (1999) Docking of Cationic Antibiotics to Negatively Charged Pockets in RNA Folds. J. Med. Chem. 42, 1250– 1261, DOI: 10.1021/jm981108g
  93
  Docking of Cationic Antibiotics to Negatively Charged Pockets in RNA Folds
  Hermann, Thomas; Westhof, Eric
  Journal of Medicinal Chemistry (1999), 42 (7), 1250-1261CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  The binding of aminoglycosides to RNA provides a paradigm system for the anal. of RNA-drug interactions. The electrostatic field around three-dimensional RNA folds creates localized and defined neg. charged regions which are potential docking sites for the cationic ammonium groups of aminoglycosides. To explore in RNA folds the electroneg. pockets suitable for aminoglycoside binding, we used calcns. of the electrostatic field and Brownian dynamics simulations of cation diffusion. We applied the technique on those RNA mols. exptl. known to bind aminoglycosides, namely, two tobramycin aptamers: the aminoglycoside-binding region in 16S rRNA and the TAR RNA from human immunodeficiency virus. For the aptamers and rRNA, for which the binding sites of the aminoglycosides are known, a good agreement between neg. charged pockets and the binding positions of the drugs was found. On the basis of variations between neomycin-like and kanamycin-like aminoglycosides in the interaction with the electrostatic field of rRNA, we propose a model for the different binding specificities of these two classes of drugs. The spatial congruence between the electroneg. pockets in RNA folds and binding positions of aminoglycosides was used to dock aminoglycosides to ribosomal and TAR RNAs. Mol. dynamics simulations were used to analyze possible RNA-drug interactions. Aminoglycosides inhibit the binding of the viral Tat protein to TAR RNA; however, the drug-binding sites are still unknown. Thus, our docking approach provides first structural models for TAR-aminoglycoside complexes. The RNA-drug interactions obsd. in the modeled complexes support the view that the antibiotics might lock TAR in a conformation with low affinity for the Tat protein, explaining the exptl. found aminoglycoside inhibition of the Tat-TAR interaction.
94. 94
  Corzana, F., Cuesta, I., Freire, F., Revuelta, J., Torrado, M., Bastida, A., Jiménez-Barbero, J., and Asensio, J. L. (2007) The Pattern of Distribution of Amino Groups Modulates the Structure and Dynamics of Natural Aminoglycosides: Implications for RNA Recognition. J. Am. Chem. Soc. 129, 2849– 2865, DOI: 10.1021/ja066348x
  94
  The Pattern of Distribution of Amino Groups Modulates the Structure and Dynamics of Natural Aminoglycosides: Implications for RNA Recognition
  Corzana, Francisco; Cuesta, Igor; Freire, Felix; Revuelta, Julia; Torrado, Mario; Bastida, Agatha; Jimenez-Barbero, Jesus; Asensio, Juan Luis
  Journal of the American Chemical Society (2007), 129 (10), 2849-2865CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  Aminoglycosides are clin. relevant antibiotics that participate in a large variety of mol. recognition processes involving different RNA and protein receptors. The 3-D structures of these polycationic oligosaccharides play a key role in RNA binding and therefore det. their biol. activity. Herein, the authors show that the particular NH2/NH3+/OH distribution within the antibiotic scaffold modulates the oligosaccharide conformation and flexibility. In particular, those polar groups flanking the glycosidic linkages have a significant influence on the antibiotic structure. A careful NMR/theor. anal. of different natural aminoglycosides, their fragments, and synthetic derivs. proves that both hydrogen bonding and charge-charge repulsive interactions are at the origin of this effect. Current strategies to obtain new aminoglycoside derivs. are mainly focused on the optimization of the direct ligand/receptor contacts. The results strongly suggest that the particular location of the NH2/NH3+/OH groups within the antibiotics can also modulate their RNA binding properties by affecting the conformational preferences and inherent flexibility of these drugs. This fact should also be carefully considered in the design of new antibiotics with improved activity.
95. 95
  Fourmy, D., Recht, M. I., Blanchard, S. C., and Puglisi, J. D. (1996) Structure of the A Site of Escherichia coli 16S Ribosomal RNA Complexed with an Aminoglycoside Antibiotic. Science 274, 1367– 1371, DOI: 10.1126/science.274.5291.1367
  95
  Structure of the A site of Escherichia coli 16S ribosomal RNA complexed with an aminoglycoside antibiotic
  Fourmy, Dominique; Recht, Michael I.; Blanchard, Scott C.; Puglisi, Joseph D.
  Science (Washington, D. C.) (1996), 274 (5291), 1367-1371CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
  Aminoglycoside antibiotics that bind to 30S ribosomal A-site RNA cause misreading of the genetic code and inhibit translocation. The aminoglycoside antibiotic paromomycin (I) binds specifically to an RNA oligonucleotide that contains the 30S subunit A site, and the soln. structure of the RNA-I complex was detd. by NMR spectroscopy. The antibiotic binds in the major groove of the model A-site RNA within a pocket created by an A-A base pair and a single bulged adenine. Specific interactions occur between aminoglycoside chem. groups important for antibiotic activity and conserved nucleotides in the RNA. The structure explains binding of diverse aminoglycosides to the ribosome, their specific activity against prokaryotic organisms, and various resistance mechanisms, and provides insight into ribosome function.
96. 96
  Zhao, F., Zhao, Q., Blount, K. F., Han, Q., Tor, Y., and Hermann, T. (2005) Moelcular Recognition of RNA by Neomycin and a Restricted Neomycin Derivative. Angew. Chem., Int. Ed. 44, 5329– 5334, DOI: 10.1002/anie.200500903
  96
  Molecular recognition of RNA by neomycin and a restricted neomycin derivative
  Zhao, Fang; Zhao, Qiang; Blount, Kenneth F.; Han, Qing; Tor, Yitzhak; Hermann, Thomas
  Angewandte Chemie, International Edition (2005), 44 (33), 5329-5334CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The preorganized presentation of functional groups in the antibiotic neomycin (green) is exploited to obtain a conformationally restricted aminoglycoside (yellow) by regioselective intramol. cyclization. X-ray crystallog. data show how the natural product and the deriv. recognize the RNA target motif that is the binding site of aminoglycoside antibiotics.
97. 97
  Blount, K. F., Zhao, F., Hermann, T., and Tor, Y. (2005) Conformational Constraint as a Means for Understanding RNA-Aminoglycoside Specificity. J. Am. Chem. Soc. 127, 9818– 9829, DOI: 10.1021/ja050918w
  97
  Conformational Constraint as a Means for Understanding RNA-Aminoglycoside Specificity
  Blount, Kenneth F.; Zhao, Fang; Hermann, Thomas; Tor, Yitzhak
  Journal of the American Chemical Society (2005), 127 (27), 9818-9829CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  The lack of high RNA target selectivity displayed by aminoglycoside antibiotics results from both their electrostatically driven binding mode and their conformational adaptability. The inherent flexibility around their glycosidic bonds allows them to easily assume a variety of conformations, permitting them to structurally adapt to diverse RNA targets. This structural promiscuity results in the formation of aminoglycoside complexes with diverse RNA targets in which the antibiotics assume distinct conformations. Such differences suggest that covalently linking individual rings in an aminoglycoside could reduce its available conformations, thereby altering target selectivity. To explore this possibility, conformationally constrained neomycin and paromomycin analogs designed to mimic the A-site bound aminoglycoside structure have been synthesized and their affinities to the TAR and A-site, two therapeutically relevant RNA targets, have been evaluated. As per design, this constraint has minimal deleterious effect on binding to the A-site. Surprisingly, however, preorganizing these neomycin-class antibiotics into a TAR-disfavored structure has no deleterious effect on binding to this HIV-1 RNA sequence. The authors rationalize these observations by suggesting that the A-site and HIV TAR possess inherently different selectivities toward aminoglycosides. The inherent plasticity of the TAR RNA, coupled to the remaining flexibility within the conformationally constrained analogs, makes this RNA site an accommodating target for such polycationic ligands. In contrast, the deeply encapsulating A-site is a more discriminating RNA target. These observations suggest that future design of novel target selective RNA-based therapeutics will have to consider the inherent "structural" selectivity of the RNA target and not only the selectivity patterns displayed by the low mol. wt. ligands.
98. 98
  Asensio, J. L., Hidalgo, A., Bastida, A., Torrado, M., Corzana, F., Chiara, J. L., Garcia-Junceda, E., Cañada, J., and Jiménez-Barbero, J. (2005) A Simple Structural-Based Approach to Prevent Aminoglycoside Inactivation by Bacterial Defense Proteins. Conformational Restriction Provides Effective Protection against Neomycin-B Nucleotidylation by ANT. J. Am. Chem. Soc. 127, 8278– 8279, DOI: 10.1021/ja051722z
  98
  A Simple Structural-Based Approach to Prevent Aminoglycoside Inactivation by Bacterial Defense Proteins. Conformational Restriction Provides Effective Protection against Neomycin-B Nucleotidylation by ANT4
  Asensio, Juan Luis; Hidalgo, Ana; Bastida, Agatha; Torrado, Mario; Corzana, Francisco; Chiara, Jose Luis; Garcia-Junceda, Eduardo; Canada, Javier; Jimenez-Barbero, Jesus
  Journal of the American Chemical Society (2005), 127 (23), 8278-8279CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  Herein, the authors describe how the conformational differences exhibited by aminoglycosides in the binding pockets of the ribosome and those enzymes involved in bacterial resistance can be exploited in the design of new antibiotic derivs. with improved activity in resistant strains. The simple modification shown in the figure, leading to the conformationally restricted 5, provides an effective protection against aminoglycoside inactivation by Staphylococcus aureus ANT4, both in vivo and in vitro.
99. 99
  Bastida, A., Hidalgo, A., Chiara, J. L., Torrado, M., Corzana, F., Pérez-Cañadillas, J. M., Groves, P., Garcia-Junceda, E., Gonzalez, C., Jimenez-Barbero, J., and Asensio, J. L. (2006) Exploring the Use of Conformationally Locked Aminoglycosides as a New Strategy to Overcome Bacterial Resistance. J. Am. Chem. Soc. 128, 100– 116, DOI: 10.1021/ja0543144
  99
  Exploring the Use of Conformationally Locked Amino-Glycosides as a New Strategy to Overcome Bacterial Resistance
  Bastida, Agatha; Hidalgo, Ana; Chiara, Jose Luis; Torrado, Mario; Corzana, Francisco; Perez-Canadillas, Jose Manuel; Groves, Patrick; Garcia-Junceda, Eduardo; Gonzalez, Carlos; Jimenez-Barbero, Jesus; Asensio, Juan Luis
  Journal of the American Chemical Society (2006), 128 (1), 100-116CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  The emergence of bacterial resistance to the major classes of antibiotics has become a serious problem over recent years. For amino-glycosides, the major biochem. mechanism for bacterial resistance is the enzymic modification of the drug. Interestingly, in several cases, the oligosaccharide conformation recognized by the ribosomic RNA and the enzymes responsible for the antibiotic inactivation is remarkably different. This observation suggests a possible structure-based chem. strategy to overcome bacterial resistance; in principle, it should be possible to design a conformationally locked oligosaccharide that still retains antibiotic activity but that is not susceptible to enzymic inactivation. To explore the scope and limitations of this strategy, we have synthesized several amino-glycoside derivs. locked in the ribosome-bound "bioactive" conformation. The effect of the structural pre-organization on RNA binding, together with its influence on the amino-glycoside inactivation by several enzymes involved in bacterial resistance, has been studied. Our results indicate that the conformational constraint has a modest effect on their interaction with rRNA. In contrast, it may display a large impact on their enzymic inactivation. Thus, the work presented herein provides a key example of how the conformational differences exhibited by these ligands within the binding pockets of the ribosome and of those enzymes involved in bacterial resistance can, in favorable cases, be exploited for designing new antibiotic derivs. with improved activity in resistant strains.
100. 100
  Revuelta, J., Vacas, T., Bastida, A., and Asensio, J. L. (2010) Structure-Based Design of Highly Crowded Ribostamycin/Kananmycin Hybrids as a New Family of Antibiotics. Chem. - Eur. J. 16, 2986– 2991, DOI: 10.1002/chem.200903003
  100
  Structure-Based Design of Highly Crowded Ribostamycin/Kanamycin Hybrids as a New Family of Antibiotics
  Revuelta, Julia; Vacas, Tatiana; Corzana, Francisco; Gonzalez, Carlos; Bastida, Agatha; Asensio, Juan Luis
  Chemistry - A European Journal (2010), 16 (10), 2986-2991, S2986/1-S2986/8CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The 2-deoxystreptamine (2-DOS) ring of aminoglycoside pseudodisaccharide fragment I/II was modified with a neutral ribose (ring IV) unit and pyranose unit (xylosamine and glucose, ring III) at positions 5 and 6 of the 2-DOS ring, resp., providing hybrids between the 4,5- and 4,6-DOS subfamilies. The resultant pseudotetrasaccharides and natural parent compds. neamine (1), ribostamycin (2), kanamycin-B (3) and kanamycin-A (4) were evaluated for rRNA binding and MIC values against E. coli (DH5α). The simultaneous presence of ribose and glucose at positions 5 and 6 of the 2-DOS ring led to a significant increase in both both Kd (dissocn. const. of ligand/RNA complex) and MIC; replacement of glucose by xylose, however, produces dramatic improvement in both Kd and MIC.
101. 101
  Herzog, I. M., Louzoun Zada, S., and Fridman, M. (2016) Effects of 5-O-Ribosylation of Aminoglycosides on Antimicrobial Activity and Selective Perturbation of Bacterial Translation. J. Med. Chem. 59, 8008– 8018, DOI: 10.1021/acs.jmedchem.6b00793
  101
  Effects of 5-O-Ribosylation of Aminoglycosides on Antimicrobial Activity and Selective Perturbation of Bacterial Translation
  Herzog, Ido M.; Louzoun Zada, Sivan; Fridman, Micha
  Journal of Medicinal Chemistry (2016), 59 (17), 8008-8018CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  We studied six pairs of aminoglycosides and their corresponding ribosylated derivs. synthesized by attaching a β-O-linked ribofuranose to the 5-OH of the deoxystreptamine ring of the parent pseudooligosaccharide antibiotic. Ribosylation of the 4,6-disubstituted 2-deoxystreptamine aminoglycoside kanamycin B led to improved selectivity for inhibition of prokaryotic relative to eukaryotic in vitro translation. For the pseudo-disaccharide aminoglycoside scaffolds neamine and nebramine, ribosylated derivs. were both more potent antimicrobials and more selective to inhibition of prokaryotic translation. Based on the results of this study we suggest that modification of the 5-OH position of the streptamine ring of other natural or semi-synthetic pseudo-disaccharide aminoglycoside scaffolds contg. an equatorial amine at the 2' sugar position with a β-O-linked ribofuranoside is a promising avenue for the development of novel aminoglycoside antibiotics with improved efficacy and reduced toxicity.
102. 102
  Asako, T., Yoshioka, K., Mabuchi, H., and Hiraga, K. (1978) Chemical Transformation of 3′-Chloro-3′-deoxyaminoglycosides into New Cyclic Pseudo-trisaccharides. Heterocycles 11, 197– 2002, DOI: 10.3987/S(N)-1978-01-0197
  102
  Chemical transformation of 3'-chloro-3'-deoxyaminoglycosides into new cyclic pseudo-trisaccharides
  Asako, Tsunehiko; Yoshioka, Kouichi; Mabuchi, Hiroshi; Hiraga, Kentaro
  Heterocycles (1978), 11 (), 197-202CODEN: HTCYAM; ISSN:0385-5414.
  Treatment of the aminoglycosides [I; R = H, H2NCH2CH2CH(OH)CO; R1 = Cl, R2 = H] with a base gave cyclic pseudotrisaccharides II as the major products and I (R as before, R1 = H, R2 = OH) as the minor products.
103. 103
  Morgenthaler, M., Schweizer, E., Hoffmann-Roder, A., Benini, F., Martin, R. E., Jaeschke, G., Wagner, B., Fischer, H., Bendels, S., Zimmerli, D., Schneider, J., Diederich, F., Kansy, M., and Muller, K. (2007) Predicting and Tuning Physicochemical Properties in Lead Optimization: Amine Basicities. ChemMedChem 2, 1100– 1115, DOI: 10.1002/cmdc.200700059
  103
  Predicting and tuning physicochemical properties in lead optimization: amine basicities
  Morgenthaler, Martin; Schweizer, Eliane; Hoffmann-Roder, Anja; Benini, Fausta; Martin, Rainer E.; Jaeschke, Georg; Wagner, Bjorn; Fischer, Holger; Bendels, Stefanie; Zimmerli, Daniel; Schneider, Josef; Diederich, Francois; Kansy, Manfred; Muller, Klaus
  ChemMedChem (2007), 2 (8), 1100-1115CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. This review describes simple and useful concepts for predicting and tuning the pKa values of basic amine centers, a crucial step in the optimization of phys. and ADME properties of many lead structures in drug-discovery research. The article starts with a case study of tricyclic thrombin inhibitors featuring a tertiary amine center with pKa values that can be tuned over a wide range, from the usual value of around 10 to below 2 by (remote) neighboring functionalities commonly encountered in medicinal chem. Next, the changes in pKa of acyclic and cyclic amines upon substitution by fluorine, oxygen, nitrogen, and sulfur functionalities, as well as carbonyl and carboxyl derivs. are systematically analyzed, leading to the derivation of simple rules for pKa prediction. Electronic and stereoelectronic effects in cyclic amines are discussed, and the emerging computational methods for pKa predictions are briefly surveyed. The rules for tuning amine basicities should not only be of interest in drug-discovery research, but also to the development of new crop-protection agents, new amine ligands for organometallic complexes, and in particular, to the growing field of amine-based organocatalysis.
104. 104
  Barbieri, C. M., Kaul, M., Bozza-Hingos, M., Zhao, F., Tor, Y., Hermann, T., and Pilch, D. S. (2007) Defining the Molecular Forces That Determine the Impact of Neomycin on Bacterial Protein Synthesis: Importance of the 2-Amino Functionality. Antimicrob. Agents Chemother. 51, 1760– 1769, DOI: 10.1128/AAC.01267-06
  104
  Defining the molecular forces that determine the impact of neomycin on bacterial protein synthesis: importance of the 2'-amino functionality
  Barbieri, Christopher M.; Kaul, Malvika; Bozza-Hingos, Melanie; Zhao, Fang; Tor, Yitzhak; Hermann, Thomas; Pilch, Daniel S.
  Antimicrobial Agents and Chemotherapy (2007), 51 (5), 1760-1769CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
  2-Deoxystreptamine (2-DOS) aminoglycosides exert their antibiotic actions by binding to the A site of the 16S rRNA and interfering with bacterial protein synthesis. However, the mol. forces that govern the antitranslational activities of aminoglycosides are poorly understood. Here, we describe studies aimed at elucidating these mol. forces. In this connection, we compare the bactericidal, antitranslational, and rRNA binding properties of the 4,5-disubstituted 2-DOS aminoglycoside neomycin (Neo) and a conformationally restricted analog of Neo (CR-Neo) in which the 2'-nitrogen atom is covalently conjugated to the 5''-carbon atom. The bactericidal potency of Neo exceeds that of CR-Neo, with this enhanced antibacterial activity reflecting a correspondingly enhanced antitranslational potency. Time-resolved fluorescence anisotropy studies suggest that the enhanced antitranslational potency of Neo relative to that of CR-Neo is due to a greater extent of drug-induced redn. in the mobilities of the nucleotides at positions 1492 and 1493 of the rRNA A site. Buffer- and salt-dependent binding studies, coupled with high-resoln. structural information, point to electrostatic contacts between the 2'-amino functionality of Neo and the host rRNA as being an important modulator of 1492 and 1493 base mobilities and therefore antitranslational activities.
Supporting Information
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsinfecdis.9b00128.
- Full experimental details and copies of ¹H and ¹³C NMR spectra for all new AGAs (PDF)
- Crystallographic data (CIF)
- id9b00128_si_001.pdf (2.56 MB)
- id9b00128_si_002.cif (891.77 kb)
Terms & Conditions

Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Modification at the 2′-Position of the 4,5-Series of 2-Deoxystreptamine Aminoglycoside Antibiotics To Resist Aminoglycoside Modifying Enzymes and Increase Ribosomal Target SelectivityClick to copy article linkArticle link copied!

ACS Infectious Diseases

Abstract

Results

Chemical Synthesis

Scheme 1

Scheme 2

Scheme 3

Scheme 4

Scheme 5

Figure 1

Scheme 6

Activity and Selectivity at the Target Level

Figure 2

Antibacterial Activity in the Absence and Presence of Aminoglycoside Modifying Enzymes

Discussion

Figure 3

Conclusion

Supporting Information

Terms & Conditions

Author Information

Acknowledgments

References

Cited By

ACS Infectious Diseases

Article Views

Altmetric

Citations

Recommended Articles

Abstract

Scheme 1

Scheme 2

Scheme 3

Scheme 4

Scheme 5

Figure 1

Scheme 6

Figure 2

Figure 3

References

Supporting Information

Supporting Information

Terms & Conditions

Modification at the 2′-Position of the 4,5-Series of 2-Deoxystreptamine Aminoglycoside Antibiotics To Resist Aminoglycoside Modifying Enzymes and Increase Ribosomal Target Selectivity
Click to copy article linkArticle link copied!