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An Iterative Approach Guides Discovery of the FabI Inhibitor Fabimycin, a Late-Stage Antibiotic Candidate with In Vivo Efficacy against Drug-Resistant Gram-Negative Infections
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  • Erica N. Parker
    Erica N. Parker
    Department of Chemistry and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States
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    Orcidhttps://orcid.org/0000-0001-5982-0458
  • Brett N. Cain
    Brett N. Cain
    Department of Chemistry and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States
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  • Behnoush Hajian
    Behnoush Hajian
    Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
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  • Rebecca J. Ulrich
    Rebecca J. Ulrich
    Department of Chemistry and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States
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    Orcidhttps://orcid.org/0000-0001-6013-6565
  • Emily J. Geddes
    Emily J. Geddes
    Department of Chemistry and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States
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  • Sulyman Barkho
    Sulyman Barkho
    Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
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  • Hyang Yeon Lee
    Hyang Yeon Lee
    Department of Chemistry and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States
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  • John D. Williams
    John D. Williams
    Walter Reed Army Institute of Research, Silver Spring, Maryland 20910 United States
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    Malik Raynor
    Walter Reed Army Institute of Research, Silver Spring, Maryland 20910 United States
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  • Diana Caridha
    Diana Caridha
    Walter Reed Army Institute of Research, Silver Spring, Maryland 20910 United States
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    Angela Zaino
    Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
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    Mrinal Shekhar
    Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
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  • Kristen A. Muñoz
    Kristen A. Muñoz
    Department of Chemistry and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States
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  • Kara M. Rzasa
    Kara M. Rzasa
    Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
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    Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
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    Diana Hunt
    Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
    Department of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts 02115, United States
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  • Xiannu Jin
    Xiannu Jin
    Walter Reed Army Institute of Research, Silver Spring, Maryland 20910 United States
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    Chau Vuong
    Walter Reed Army Institute of Research, Silver Spring, Maryland 20910 United States
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    Walter Reed Army Institute of Research, Silver Spring, Maryland 20910 United States
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  • Aya M. Kelly
    Aya M. Kelly
    Department of Chemistry and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States
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  • Michael P. Mulligan
    Michael P. Mulligan
    Department of Chemistry and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States
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    Katie K. Lee
    Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
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    Gee W. Lau
    Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States
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  • Deborah T. Hung
    Deborah T. Hung
    Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
    Department of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts 02115, United States
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    Orcidhttps://orcid.org/0000-0003-4262-0673
  • Paul J. Hergenrother*
    Paul J. Hergenrother
    Department of Chemistry and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States
    *E-mail: [email protected]
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ACS Central Science

Cite this: ACS Cent. Sci. 2022, 8, 8, 1145–1158
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https://doi.org/10.1021/acscentsci.2c00598
Published August 10, 2022

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Abstract

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Genomic studies and experiments with permeability-deficient strains have revealed a variety of biological targets that can be engaged to kill Gram-negative bacteria. However, the formidable outer membrane and promiscuous efflux pumps of these pathogens prevent many candidate antibiotics from reaching these targets. One such promising target is the enzyme FabI, which catalyzes the rate-determining step in bacterial fatty acid biosynthesis. Notably, FabI inhibitors have advanced to clinical trials for Staphylococcus aureus infections but not for infections caused by Gram-negative bacteria. Here, we synthesize a suite of FabI inhibitors whose structures fit permeation rules for Gram-negative bacteria and leverage activity against a challenging panel of Gram-negative clinical isolates as a filter for advancement. The compound to emerge, called fabimycin, has impressive activity against >200 clinical isolates of Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii, and does not kill commensal bacteria. X-ray structures of fabimycin in complex with FabI provide molecular insights into the inhibition. Fabimycin demonstrates activity in multiple mouse models of infection caused by Gram-negative bacteria, including a challenging urinary tract infection model. Fabimycin has translational promise, and its discovery provides additional evidence that antibiotics can be systematically modified to accumulate in Gram-negative bacteria and kill these problematic pathogens.

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Synopsis

Fabimycin is a bacterial FabI inhibitor that possesses potent antibiotic activity against multiple ESKAPE pathogens and efficacy in several mouse infection models, while largely sparing human commensal bacteria.

Introduction

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Novel antibiotic classes for infections caused by Gram-positive pathogens have been a success story over the last 20 years, with drugs in the oxazolidinone, mutilin, and lipopeptide classes all having notable clinical or veterinary impact. (1−3) Further, there are additional antibiotics moving through clinical trials for Gram-positive infections, including new compound classes and antibiotics that engage unexploited biological targets. (4) In contrast, there has not been a novel class of antibiotics FDA approved for treatment of Gram-negative pathogens contained within the group of high-priority antibiotic-resistant, nosocomoial pathogens (ESKAPE pathogens (5,6)) in over 50 years; this situation has led to increased mortality, with these Gram-negative bacteria representing four of the top six pathogens causing antibiotic-associated deaths, and some studies showing that 75% of deaths from drug-resistant pathogens are now caused by Gram-negative bacteria. (7,8) This discovery void is largely due to the low likelihood that a given compound will accumulate inside Gram-negative bacteria, as their dense lipopolysaccharide outer membrane and promiscuous efflux pumps work in concert to prevent candidate antibiotics from reaching their target. Recent studies reveal that compounds capable of accumulating inside Gram-negative bacteria often possess certain physicochemical properties, (9−11) explaining why high-throughput screens of millions of compounds have failed to identify Gram-negative active antibiotics. (12,13)
Encouragingly, the same biological processes that are exploited through antibiotic intervention against Gram-positive bacteria can typically be leveraged to kill Gram-negative bacteria; inhibitors of protein translation, DNA replication, and cell wall biosynthesis have broad-spectrum activity (Gram-positive and Gram-negative) provided they can enter the cell and reach their target. However, many other promising biological targets have not yet been leveraged to kill Gram-negative organisms, as the antibiotics that engage these targets do not accumulate in Gram-negative bacteria. One such outstanding target is the enoyl-acyl carrier protein reductase enzyme FabI, which catalyzes the rate-determining step in bacterial fatty acid biosynthesis. (14) A lead compound (15,16) identified from a biochemical high-throughput screen for FabI inhibition was optimized into Debio-1452 (Figure 1A), the phosphonoxy methyl prodrug version of which (called afabicin) is in Phase 2 clinical trials for infections caused by Staphylococcus aureus. (17) While FabI is a promising exploitable target for problematic Gram-negative ESKAPE pathogens, including Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii, Debio-1452 does not accumulate inside these cells and is consequently inactive against these bacteria. (18)

Figure 1

Figure 1. FabI inhibitors. (A) Debio-1452 is highly potent against S. aureus; Debio-1452-NH3 retains this potency and gains modest activity against many Gram-negative pathogens. (B) The structure–activity relationship (SAR) of Debio-1452 showing regions amenable to substitution (highlighted in green) and those critical for antibacterial activity (highlighted in red).

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We recently applied an emerging understanding of the correlation between the physicochemical traits of small molecules and their accumulation in Gram-negative bacteria to design a version of Debio-1452 that is effective against these pathogens. (19) This compound, Debio-1452-NH3 (Figure 1A), has antibacterial activity against Gram-negative clinical isolates and efficacy in mouse infection models, and as such is the first member of this class to have notable Gram-negative antibacterial activity. (19) In efforts to develop a more promising clinical candidate for Gram-negative infections, we now report the use of iterative compound synthesis, clinical isolate testing, and X-ray crystallography to identify fabimycin, a FabI inhibitor with enhanced antibacterial potency, improved in vivo tolerability, and high specificity for pathogenic versus commensal bacteria. Fabimycin shows efficacy in multiple mouse infection models, including a challenging mouse model of urinary tract infection (UTI), acute pneumonia models, and several neutropenic soft tissue models of infection with Gram-negative bacteria.

Results

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Identification of Fabimycin and Its Activity against Drug-Resistant Gram-Negative Pathogens

Aided by recently described guidelines for design of Gram-negative penetrant compounds (the eNTRy rules (9,11,20)), Debio-1452-NH3 was discovered through a focused synthetic campaign and subsequent evaluation of just a handful of compounds. (19) However, to advance as a lead candidate, its therapeutic window would need to be widened, as efficacy of Debio-1452-NH3 in murine infection models with Gram-negative pathogens was observed at the maximal tolerated dose (MTD). (19) An objective was set to identify next-generation FabI inhibitors that exhibit greater potency against Gram-negative clinical isolates and better in vivo tolerability, expecting that such compounds could then be efficacious even in very challenging models and those of high translational relevance, such as a UTI model.
Our critical path for advancement included the synthesis of compounds and subsequent evaluation of antibacterial activity against Gram-negative clinical isolates to prioritize leads, followed by evaluation of toxicity, pharmacokinetics, and ultimately efficacy in mouse infection models. Compound design was guided by the co-crystal structure of Debio-1452 with FabI (from S. aureus) (21) and the established structure–activity relationship (SAR) for this compound class, both of which point to the immutability of the N-methyl acrylamide (E configuration) and the H-bond donor/acceptor pair on the naphthyridinone ring system that interacts with key amino acid residues within the FabI active site (Figure 1B). (22−24) In contrast, the position adjacent to the carbonyl of the naphthyridinone ring was judged to be highly solvent-exposed; additionally, other ring systems were considered as replacements for the benzofuran (Figure 1B). This analysis was instrumental for informing the proper placement of a positively charged amine to facilitate accumulation in Gram-negative bacteria but not disrupt target engagement. Given the X-ray and SAR data, and lessons learned from previous identification of Debio-1452-NH3, priority compounds were envisioned with a variety of amines and ring systems proximal to the carbonyl of the lactam.
A modular and convergent synthesis was designed leveraging a Heck coupling of acrylamide 1 with bromo functionalized acylaminopyridine rings which upon deprotection provided the final compounds (Figure 2). Brominated coupling partners were designed to give final compounds that maintained the necessary N/NH arrangement for engagement with FabI and contained the basic amine required for Gram-negative accumulation. To quickly interrogate the solvent-exposed region of the scaffold adjacent to the lactam carbonyl, ring size and shape were altered. Specifically, a series comprising four-membered ring spirocycles (2–4), six-membered ring spirocycles (5, 6), and azepanones (7–9) was constructed.

Figure 2

Figure 2. Debio-1452 analogue synthesis and antibacterial activity. The general synthetic route utilized to synthesize amine-containing compounds, and their antimicrobial activities against Gram-positive and Gram-negative bacteria. (†) indicates dose-independent trailing growth observed; see Supporting Information, Extended Data Figure S1. MIC values were determined using the microdilution broth method, as outlined by CLSI. All experiments were performed in biological triplicate. E. coli ΔtolC = JW5503.

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The compounds synthesized, shown in Figure 2, were evaluated against Gram-positive and Gram-negative reference strains (S. aureus ATCC 29213 and E. coli MG1655, respectively), as well as an efflux-deficient E. coli strain (ΔtolC, JW5503). While compounds (±)-4, (±)-5, (±)-6, and (±)-9 all had reduced antibacterial activity against E. coli MG1655 relative to Debio-1452-NH3, compounds 2, (±)-3, (±)-7, and (±)-8 maintained good activity (Figure 2) and were thus chosen for further evaluation. A panel of 10 clinical isolates was selected where Debio-1452-NH3 had previously demonstrated only minimal potency (MIC values of 16 or 32 μg/mL), including two E. coli, four K. pneumoniae, and four A. baumannii strains. (19) As expected, Debio-1452 has no activity against this Gram-negative “challenge panel”, and Debio-1452-NH3 has only minimal activity (Figure 2). Assessment of 2, (±)-3, (±)-7, and (±)-8 revealed more potent activity for all four compounds relative to Debio-1452-NH3, with the ε-caprolactam (±)-7 emerging as a promising candidate. This compound possessed superior activity against the clinical isolate challenge panel with all strains inhibited at ≤8 μg/mL. Two derivatives were constructed where the amine-decorated ε-caprolactam was coupled to alternative ring systems, substituting out the benzofuran, but neither of these compounds provided an improvement in activity (Extended Data, Figure S2).
The two enantiomers of (±)-7 were separated by chiral preparatory HPLC, and biological assessment revealed the (−) enantiomer to possess significantly greater antibacterial activity than the (+) enantiomer. X-ray crystallography studies, described later herein, were used to determine that the highly active (−) enantiomer possesses the S stereochemical configuration. As shown in Figure 2, (S)-7, coined fabimycin, (25–27) has outstanding activity against S. aureus and E. coli ΔtolC, an MIC value of 2 μg/mL against E. coli MG1655, and very good activity against the clinical isolate challenge panel, whereas (R)-7 is significantly less active.
To probe the influence of the amine on antibacterial activity and compound accumulation, two additional derivatives were synthesized: compound 10, with the expanded ring system but lacking the amine, and compound (S)-11, a carbamylated version of fabimycin. Of note, 10 and (S)-11 both lack a primary amine. While both compounds display modest inhibition of purified bacterial FabI (Extended Data, Figure S3) and excellent antimicrobial activity against reference strains, they have diminished activity against Gram-negative clinical isolates (Figure 2). Furthermore, when assessed in a whole-cell accumulation assay (28) in E. coli, 10 displayed reduced whole-cell accumulation consistent with its reduction in antibacterial activity (Extended Data, Figure S4). In contrast, other amine-containing compounds in Figure 2 show significant whole-cell accumulation in E. coli (Extended Data, Figure S4) (the limited aqueous solubility of (S)-11 prevented it from being assessed in this assay).
An interesting aspect of FabI as an antibacterial target is the possibility for a relatively narrow spectrum of activity when compared to that observed with most antibiotics (e.g., inhibitors of protein synthesis, DNA replication, and/or cell wall biosynthesis). For example, it has been noted that ESKAPE pathogen P. aeruginosa possesses the FabV isoform, meaning inhibition of FabI will not be lethal in this pathogen. (29) Certain Gram-positive pathogens (Streptococcus sp. and Enterococcus sp.) and commensal bacteria are also not reliant on FabI and thus are expected to be insensitive to FabI inhibition, suggesting that FabI inhibitors could be microbiome-sparing. (30−32) To explore this possibility, fabimycin was assessed against a panel of pathogens possessing alternate enoyl-acyl carrier protein reductases as well as anaerobic human commensal bacterial species. (33−35) In all cases, low/no antibacterial activity was observed against the strains assessed (n = 41), demonstrating the specificity of this FabI inhibitor and its potential for minimal perturbation of the microbiome (Table 1).
Table 1. Spectrum of Fabimycin Activitya
a

MIC experiments with commensal bacteria and pathogenic bacteria possessing alternate enoyl-acyl carrier protein reductases (29,31,36) indicate these strains are not susceptible to fabimycin.

Given its promising antibacterial activity, fabimycin was advanced through a battery of mechanistic and translational experiments. While separation of (±)-7 on a preparative chiral column was suitable to obtain the quantities of fabimycin required for studies such as MIC assays, it was necessary to optimize the synthetic route to enable scale-up and obtain quantities of the fabimycin required for detailed in vivo tolerability, pharmacokinetic analysis, and efficacy experiments. To this end, the synthetic route shown in Figure 3 was developed and employed to generate gram-scale quantities of enantiopure fabimycin.

Figure 3

Figure 3. Optimized synthesis of fabimycin. The synthetic route used to access gram-scale quantities of fabimycin, utilizing dynamic kinetic resolution (DKR) to install the critical stereogenic center.

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The route proceeds through condensation of quinolone 12 with hydroxylamine, followed by activation of the resulting oxime (13) via treatment with mesyl chloride to generate compound 14 in good yield. After forming azepanone 15 through a Beckmann rearrangement, molecular bromine was used to produce aryl bromide 16. Alpha-iodination of 16 provided dihalogenated 17 in good yield, and compound 17 was subjected to azidation and subsequent Staudinger reduction to afford amine 18. This amine was the key intermediate for enantioenrichment via a dynamic kinetic resolution (DKR), proceeding through epimerization of the amine via imine formation with 2-hydroxy-5-nitrobenzaldehyde followed by selective crystallization with l-pyroglutamic acid. (37) Optimization of this critical step involved significant screening (Extended Data, Figure S5). After enantioenrichment (up to 99.5% ee), amine 19 was protected to afford compound 20 (ee maintained) and used in a Heck coupling with acrylic amide 1 to produce 11, which, when subjected to acidic conditions, liberated fabimycin.
Fabimycin was assessed for its antibacterial activity against a panel of multidrug-resistant A. baumannii, E. coli, and K. pneumoniae clinical isolates (54 strains in total). As shown in Figure 4A, fabimycin is markedly more potent than Debio-1452 and Debio-1452-NH3 against all the Gram-negative clinical isolates. All three compounds also maintain high potency versus panels of S. aureus clinical isolates (Figure 4A and Extended Data, Figure S6).

Figure 4

Figure 4. Antimicrobial activity of fabimycin against clinical isolates. (A) The susceptibility of clinical isolates (Gram-negative species and S. aureus) to fabimycin, Debio-1452-NH3, and Debio-1452. MICs performed in biological triplicate. (B) Further exploration of the breadth of fabimycin’s antibacterial activity against diverse clinical isolate panels of K. pneumoniae and A. baumannii, as compared to levofloxacin. MICs performed in biological duplicate.

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As the greatest improvement in activity of fabimycin (relative to Debio-1452-NH3) was against K. pneumoniae and A. baumannii clinical isolates, fabimycin was further assessed against more diverse and expansive clinical isolate panels of these two pathogens to determine the MIC50 and MIC90 values. Excitingly, when assessed against a panel of 100 K. pneumoniae clinical isolates, fabimycin inhibited 90% of the strains at 4 μg/mL, relative to 32 μg/mL for levofloxacin (Figure 4B). Also encouraging was the narrow MIC range for fabimycin, suggesting that intrinsic resistance to this compound is not prevalent in existing bacterial populations. The analogous data in 100 A. baumannii clinical isolates, a panel specifically curated to represent the genomic diversity of the species (38) including 27 multidrug-resistant strains, 35 extensively drug-resistant strains, and 1 pan-resistant strain (fabimycin MIC = 1 μg/mL), are also promising, with fabimycin exhibiting a MIC90 value of 8 μg/mL (relative to 32 μg/mL for levofloxacin) and a narrow distribution of MIC values (Figure 4B).

Mode of Action

Spontaneous resistant mutants to fabimycin were generated in E. coli MG1655, A. baumannii 19606, and S. aureus ATCC 29213 at 8×, 16×, and 32× the respective MICs with low frequencies of resistance observed at 8×–16× the MIC for all pathogens (Figure 5A). Importantly, sequencing of the fabI gene in resistant colonies revealed mutations encoding single amino acid changes within the active site of FabI (Figure 5B). While several FabI mutations were observed in fabimycin-resistant A. baumannii, the MIC of the bacteria harboring mutant FabI was often near fabimycin concentrations attained in vivo (as shown later). In E. coli, the most frequently observed FabI mutation to arise in fabimycin-resistant colonies was at G148 (Figure 5B); E. coli with mutations at this position in FabI have been previously shown to have attenuated fitness. (19) Encouragingly, the mutant prevention concentration (MPC, the concentration where no resistant mutants are observed) of fabimycin versus E. coli was found to be 64 μg/mL and, impressively, in S. aureus, the MPC was 0.125 μg/mL. A serial passaging experiment of E. coli MG1655 in the presence of a subinhibitory concentration of fabimycin over the course of 21 days led to an 8-fold increase in the MIC for fabimycin, relative to a 128-fold increase in the MIC of ciprofloxacin in the same experiment (Extended Data, Figure 7A). To investigate the rate of killing, a time–kill growth curve was generated that revealed fabimycin slowly kills E. coli over the course of 8 h (Extended Data, Figure 7B); however, fabimycin was not profoundly bactericidal in this experiment, mimicking its progenitor’s (Debio-1452) behavior in S. aureus. (21)

Figure 5

Figure 5. Fabimycin mode of action studies. (A) Spontaneous resistance frequencies of S. aureus, E. coli, and A. baumannii versus fabimycin. Data represent three replicates for each pathogen with error bars representing the SEM. (B) Point mutations in FabI observed in fabimycin-resistant colonies, and the corresponding MIC values of fabimycin versus the mutants. All MICs were performed in biological triplicate.

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Crystallography, Molecular Dynamics, and Biophysics

An interesting feature of fabimycin is its considerably enhanced antibacterial activity relative to its enantiomer (R)-7. Assessment in E. coli reveals that each enantiomer accumulates intracellularly to a similar extent (Extended Data, Figure S4). In contrast, evaluation of the two enantiomers in the FabI activity assay shows a significant differential between the two enantiomers (Extended Data, Figure S8), with fabimycin being at least five-fold more potent against A. baumannii and E. coli FabI. Of note, in this enzyme assay IC50 values cannot be accurately determined below ∼10 nM, so the value for fabimycin likely under-represents its biochemical potency. Taken together, the data suggest that the diminished antibacterial activity of (R)-7 relative to fabimycin is due to reduced target engagement and not differential intracellular accumulation.
To further investigate the molecular basis for the observed differential activity between enantiomers, X-ray crystal structures of fabimycin and its enantiomer (R)-7 bound to both E. coli and A. baumannii FabI with NADH cofactor were solved with resolutions ranging from 1.5 to 2.7 Å. The general binding mode of the compounds is similar to what has been previously reported for this class of compounds and Debio-1452 in particular. (39) In complex with E. coli FabI, the pyridoazepanone ring forms two hydrogen bonds with the backbone carbonyl and amide nitrogen of conserved residue Ala95 (Figure 6A,B). A water-mediated interaction is also observed between the carbonyl of the lactam and the backbone amide of Gly97. Additionally, a hydrogen bond is formed between the acrylamide linker carbonyl and the conserved residue Tyr156. The benzopyran ring is nestled in a hydrophobic pocket formed by conserved, hydrophobic residues Tyr146, Pro191, Ile153, Met206, and Phe203.

Figure 6

Figure 6. Co-crystal structures of fabimycin and its enantiomer with FabI. (A) Co-crystal structure of fabimycin with E. coli FabI with NADH cofactor (PDB 7UMW). (B) Co-crystal structure of (R)-7 in E. coli FabI with NADH cofactor (7UM8). (C) Water network surrounding fabimycin in the E. coli FabI active site. (D) Water network surrounding (R)-7 in the E. coli FabI active site.

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Similar to E. coli, the hydrogen-bonding network of the pyridoazepanone ring, interactions of the acrylamide carbonyl, and the position of the flanking benzofuran ring are maintained with the analogous amino acid residues in A. baumannii FabI (Extended Data, Figure S9A,B). While no significant changes of the interacting residues can be seen between fabimycin and (R)-7 in A. baumannii FabI, the enhanced resolution of the E. coli crystal structures captures a more nuanced and detailed binding mode. In the E. coli structure, a large water network is observed between the ligand, NADH cofactor, and FabI enzyme. While this network exists in the binding of both enantiomers, it is larger and more tightly structured in the fabimycin co-crystal (see Figure 6C,D).
Intrigued by the relative similarity of the crystal structures, experiments were conducted to evaluate the stability and dynamics of the inhibitor-enzyme complex as well as the strain energy of each enantiomer. The established E. coli co-crystal structure was utilized for computational studies which determined that the less active (R)-enantiomer is more strained relative to fabimycin (∼8.30 kcal/mol higher) in the active site. This is reflected in molecular dynamic simulations that reveal the (R)-enantiomer to be much more flexible in the binding pocket of FabI leading to overall less-productive hydrogen-bond interactions with critical surrounding residues such as Ala95 and Tyr156 (Figure 7A). Isothermal titration calorimetry (ITC) was used to confirm the nanomolar potency of each compound and showed a doubling in enthalpy for fabimycin relative to the less active enantiomer (Figure 7B). Finally, differential scanning fluorimetry (DSF) experiments show that fabimycin enhances the stability of the enzyme–inhibitor complex significantly more than the less active enantiomer in both E. coli and A. baumannii versions of FabI (Figure 7B).

Figure 7

Figure 7. Computational and biophysical evaluation of fabimycin and its enantiomer. (A) Molecular dynamic simulations of fabimycin and its enantiomer using the co-crystal structures in E. coli FabI, demonstrating the enhanced flexibility (decreased stability) of (R)-7. (B) The determined enthalpy changes upon binding to FabI as assessed by isothermal titration calorimetry (ITC), as well as observed stabilization in a differential scanning fluorimetry assay of FabI (from E. coli and A. baumannii) upon compound binding relative to the holoenzyme. Tm values are means of technical triplicates with error shown as the standard deviation.

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In Vivo Experiments

Given the low resistance frequency and promising data with >200 Gram-negative clinical isolates, experiments were conducted to probe the suitability of fabimycin for in vivo infection models. As a prelude to these studies, fabimycin was evaluated against three human cell lines (HFF-1, A549, HepG2) and for its ability to lyse human red blood cells. These studies revealed fabimycin to be less cytotoxic relative to Debio-1452-NH3 and nonhemolytic even at high concentrations (200 μM, Extended Data, Table S1). Fabimycin also has lower activity against the hERG ion channel relative to both Debio-1452 and Debio-1452-NH3, and lower plasma protein binding relative to Debio-1452 (Extended Data, Table S1). Formulation and MTD studies were performed, and in all cases fabimycin was found to be better tolerated in mice with an MTD of >200 mg/kg (IP injection) relative to 50 mg/kg for Debio-1452-NH3 (Extended Data, Table S2).
An interesting aspect of this compound class is the metabolic instability in mice leading to suboptimal pharmacokinetics; (24) indeed, assessment of fabimycin in mouse, rat, and human plasma showed considerable instability in mouse plasma contrasted with excellent stability in rat and human plasma (Figure 8A). While this data suggests the possibility that antibacterial activity could improve as fabimycin moves toward humans, it does complicate the evaluation of this compound class in murine infection models. Thus, as a prelude to efficacy experiments in mouse infection models, a pharmacokinetic study was conducted with fabimycin using neutropenic female BALB/c mice infected with drug-resistant A. baumannii (fabimycin MIC = 2 μg/mL) where single doses of the compound (20, 50, 75, 100 mg/kg) were administered intravenously to the infected mice and blood taken over the course of 8 h. Encouragingly, when dosed at 75 mg/kg, fabimycin concentrations stayed above the MIC for the infectious strain for over 6 h in the thigh tissue with the Cmax nearing the MPC for wild-type E. coli when dosed at 100 mg/kg (Extended Data, Figure S10).

Figure 8

Figure 8. Plasma stability and in vivo efficacy of fabimycin. (A) Assessment of fabimycin stability in plasma. Data shown as the mean and standard deviation from two experiments. (B) Acute pneumonia infections initiated in CD-1 mice with A. baumannii AR-0299 (1.6 × 108 CFUs per mouse intranasally). Mice were treated with vehicle (8 mice) or FabI inhibitor (8 mice per group) 4, 23, and 41 h postinfection (50 mg/kg intramuscular) and the bacterial burden evaluated at 48h postinfection. (C) Neutropenic mouse thigh infection initiated in CD-1 mice with A. baumannii AR-0299 (1.22 × 106 CFUs per mouse intramuscular in thigh) were treated with vehicle (8 mice) or FabI inhibitor (8 mice per group) 2, 6, and 11 h postinfection (50 mg/kg intramuscular), and the bacterial burden was evaluated 26h postinfection. (D) Neutropenic mouse thigh infection initiated in CD-1 mice with S. aureus USA300 LAC (2.3 × 106 CFU per mouse intramuscular in thigh) were treated with vehicle (eight mice) or FabI inhibitor (eight mice per group) 2 and 7 h postinfection (5 mg/kg retro-orbital IV), and the bacterial burden was evaluated 24 h postinfection. Debio-1452-tosylate used. FabI inhibitors formulated with 20% SBE-β-CD in H2O. In B, C, and D statistical significance was determined by one-way ANOVA with Tukey’s multiple comparisons. NS, not significant. ****P < 0.0001. Error bars represent standard deviation.

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With formulation, MTD, and pharmacokinetic data in hand, the efficacy of fabimycin was evaluated in murine infection models. To start, a comparative assessment was made of fabimycin and Debio-1452-NH3 in two murine infection models using a dosing regimen (50 mg/kg, intramuscular) near the MTD for Debio-1452-NH3 but well below the MTD for fabimycin. Using an extensively drug-resistant A. baumannii clinical isolate, fabimycin outperformed Debio-1452-NH3 in both lung and neutropenic thigh infection models and achieved a >3-fold decrease in log(CFU/lung) and >2-fold decrease log(CFU/thigh) relative to the vehicle (Figure 8B,C). In a S. aureus (MRSA clinical isolate) neutropenic thigh infection model fabimycin showed significantly greater reduction of bacterial burden relative to Debio-1452 when both were administered at the low dose of 5 mg/kg (Figure 8D). As the goal of these initial models was simply to assess efficacy compared to progenitor compounds, fabimycin dosing was not maximized or optimized. To address this, fabimycin was evaluated in an experiment where neutropenic, A. baumannii-infected mice were treated four times a day (via IV injection) with doses spanning 1.25–75 mg/kg. In this experiment, significant dose-dependent responses were observed beginning at 30 mg/kg (Extended Data, Figure S11A). When using the most efficacious dose (75 mg/kg, four times a day) in a murine neutropenic thigh infection experiment with an extensively resistant NDM-1 containing strain of A. baumannii, fabimycin was able to reduce bacterial burden by nearly 2 log(CFU/thigh) (Extended Data, Figure S11B).
With an effective dose established, we aimed to evaluate fabimycin in a murine model of an infection with high translational value. Urinary tract infections (UTIs) represent one of the biggest risks for healthy individuals in terms of exposure to antibiotic-resistant bacteria with many individuals contracting one in their lifetime (roughly 1 in 2 women and 1 in 10 men); (40) UTIs caused by Gram-negative pathogens, particularly those that are drug-resistant, are becoming more frequent and remain a major clinical challenge. (40−42) As E. coli is the causative agent in the vast majority of UTIs, (43) fabimycin was evaluated in a murine UTI model with a challenging, extensively drug-resistant strain of carbapenem-resistant E. coli (fabimycin MIC = 2 μg/mL). When intravenously dosed at 33.3 mg/kg, three times a day, fabimycin was able to achieve 3.0, 2.8, 2.9, and 1.9 log10 reductions in bacterial load relative to the vehicle in the spleen, bladder, liver, and kidney tissues, respectively (Figure 9). Dose fractionation studies in infected mice also revealed other dosing regiments to be effective in reducing the bacterial load to a significant extent in mouse tissue (Figure 9 and Extended Data, Figure S12).

Figure 9

Figure 9. In vivo efficacy of fabimycin in a murine UTI model. After inducing diuresis, infection initiated in C3H/HeJ mice (8 per arm, 1.38 * 109 CFU/mouse transurethral) with E. coli AR-0055 and treated with fabimycin (IV) at varying concentrations three times daily with bacterial enumeration at 168h postinfection. Fabimycin formulated in 17% Cremophor EL, 3% SBE-β-CD in H2O which was the formulation used in the vehicle arm (administered intravenously on the same schedule as fabimycin). Colistin was formulated in H2O with 0.9% NaCl and administered subcutaneously. Percentage in red indicates the percentage of animals with bacterial counts below the limit of detection (LOD, indicated by the dotted horizontal line). In A─D statistical significance was determined by one-way ANOVA with Tukey’s multiple comparisons. NS, not significant. *P = 0.0243, ***P < 0.001, ****P < 0.0001. Data represented as the mean with s.e.m.

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Discussion

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There is a rich history in antibacterial drug discovery of identifying and advancing chemical matter arising from whole-cell phenotypic screens. In contrast, while biochemical screens have uncovered a wealth of scaffolds with promising activity, there has typically been less interest in such compounds due to the documented inability to imbue them with whole-cell antibacterial activity. (12,13) In this context, Debio-1452 is an interesting case study as it was developed from a progenitor compound that had only biochemical FabI inhibitory activity─it was first converted into a S. aureus-specific drug (Debio-1452), then to Debio-1452-NH3, and now into fabimycin, which possesses promising activity against important Gram-negative pathogens.
Relative to Debio-1452-NH3, fabimycin has significantly improved activity against A. baumannii, even surpassing the potency increase observed versus E. coli, consistent with the notion that certain FabI inhibitors can be tuned for specific bacterial homologues of FabI if the creation of pathogen-specific antibiotics is of interest. (14) The generated X-ray co-crystal structures of fabimycin bound to A. baumannii and E. coli FabI reveal that key hydrogen-bonding interactions are conserved between the two forms of the enzyme, but no significant protein conformational differences in the active site. Given the limitations of the FabI enzymatic assay when evaluating compounds possessing low nanomolar potency, use of multiple biochemical techniques will be critical to the understanding of current and future FabI inhibitors. Overall, a combination of biochemical, structural, biophysical, and computational approaches was used to better understand the differences in whole-cell activity of fabimycin and (R)-7. Biochemical assessment of the inhibitory activities of fabimycin and (R)-7 showed modest differences in potency against purified E. coli FabI (4.75-fold), whereas the differences in MIC activity between the two enantiomers in Gram-negative clinical isolates is much more significant (64–128 fold). Comparison of the co-crystal structures of fabimycin and (R)-7 reveals a more expansive and tightly structured water network in the fabimcyin structure. This result is consistent with ITC data showing fabimycin to have a more favorable binding entropy, DSF results showing a larger change in melting temperature upon compound binding to FabI relative to the less-active (R)-7, and with molecular dynamic simulations showing fabimycin to be much less strained (i.e., more stable) in the E. coli FabI active site. Taken together, these results suggest that the differences in whole-cell activity between the two enantiomers is primarily due to a more favorable water interaction network and higher degree of protein and ligand stability for fabimycin.
Beyond Gram-negative activity, the ability of fabimycin to retain approximately equivalent activity as Debio-1452 against S. aureus is impressive, as Debio-1452 was optimized to treat S. aureus infections and has thus set a high bar for potency versus this pathogen, both in vitro and in vivo. (17,44,45) The very low frequency of resistance (1.8 × 10–10 to 5.2 × 10–10, likely due at least in part to critical interactions with the amide backbone of FabI), (14,46) outstanding performance in the serial passage experiment, and the extremely low mutation prevention concentration (0.125 μg/mL) suggest great promise for fabimycin against S. aureus, as the MPC is dwarfed by the concentration of fabimycin achieved in mouse plasma (Cmax = 47 μg/mL, t1/2 = 1.4 h).
Inhibition of FabI is attractive due to its orthogonality (relative to the mammalian fatty acid biosynthetic analogue) and its essential nature, for certain bacteria, in the maintenance of cellular membranes. (47,48) The nature of the FabI target is such that its inhibition will not be lethal to all types of bacteria, as many bacteria have redundant enzymes or can compensate by exogenous fatty acid uptake; (30) indeed, fabimycin has virtually no whole-cell activity versus a sampling of such species. While this includes some pathogenic bacteria, such as P. aeruginosa, it also includes many commensal bacteria, suggesting that a suitable FabI inhibitor could be less damaging to the gut microbiome than the typical broad-spectrum antibiotic. (32) In this vein, the activity of fabimycin against UTIs is very promising, given how antibiotic treatment of UTIs is known to trigger Clostridioides difficile infection (49) and the recently described “gut–bladder axis” in recurrent UTIs. (50,51)
Similar to fusidic acid and some other antibiotics, (52,53) the advancement of this class of FabI inhibitors has been complicated by the uniquely poor stability of these compounds in mouse plasma. Given the promising activity of fabimycin in mouse infection models and encouraging data that fabimycin is dramatically more stable in rat and human plasma, it is reasonable to believe that fabimycin efficacy may improve as it is used to treat infections in higher organisms. The potency of fabimycin, combined with the very low resistance frequency and apparent lack of pre-existing resistance, bodes well for its translation.

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  • Corresponding Author
  • Authors
    • Erica N. Parker - Department of Chemistry and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States;  Orcidhttps://orcid.org/0000-0001-5982-0458
    • Brett N. Cain - Department of Chemistry and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States
    • Behnoush Hajian - Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
    • Rebecca J. Ulrich - Department of Chemistry and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States;  Orcidhttps://orcid.org/0000-0001-6013-6565
    • Emily J. Geddes - Department of Chemistry and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States
    • Sulyman Barkho - Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
    • Hyang Yeon Lee - Department of Chemistry and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States
    • John D. Williams - Walter Reed Army Institute of Research, Silver Spring, Maryland 20910 United States
    • Malik Raynor - Walter Reed Army Institute of Research, Silver Spring, Maryland 20910 United States
    • Diana Caridha - Walter Reed Army Institute of Research, Silver Spring, Maryland 20910 United States
    • Angela Zaino - Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
    • Mrinal Shekhar - Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
    • Kristen A. Muñoz - Department of Chemistry and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States
    • Kara M. Rzasa - Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
    • Emily R. Temple - Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
    • Diana Hunt - Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States;  Department of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts 02115, United States
    • Xiannu Jin - Walter Reed Army Institute of Research, Silver Spring, Maryland 20910 United States
    • Chau Vuong - Walter Reed Army Institute of Research, Silver Spring, Maryland 20910 United States
    • Kristina Pannone - Walter Reed Army Institute of Research, Silver Spring, Maryland 20910 United States
    • Aya M. Kelly - Department of Chemistry and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States
    • Michael P. Mulligan - Department of Chemistry and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States
    • Katie K. Lee - Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
    • Gee W. Lau - Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States;  Orcidhttps://orcid.org/0000-0002-7962-3950
    • Deborah T. Hung - Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States;  Department of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts 02115, United States;  Orcidhttps://orcid.org/0000-0003-4262-0673
  • Author Contributions

    E.N.P. and B.N.C. contributed equally.

  • Notes
    The authors declare the following competing financial interest(s): The University of Illinois and the Broad Institute have filed patents on some compounds described herein.

Acknowledgments

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This work was supported by the University of Illinois and the NIH (AI136773 to P.J.H. and G.W.L.). K.A.M. and M.P.M. are members of the NIH Chemistry–Biology Interface Training Grant (T32-GM136629). R.J.U. is supported by an NIH Ruth Kirschstein Award (F31AI161953) and was an NSF predoctoral fellow. This work utilized NIAID’s suite of preclinical services for in vitro and in vivo assessment (Contract Numbers HHSN272201700020I_75N93021F00001, HHSN272201700020I_75N93021F00002, and 75N93019D00022_75N93020F00001). The Collaborative Hub for Early Antibiotic Discovery (CHEAD) is grateful for financial support from the Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X). This work was supported by a gift from Anita and Josh Bekenstein and by funding provided under Cooperative Agreement #IDSEP160030-01-00 from Biomedical Advanced Research and Development Authority (BARDA). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of The Assistant Secretary for Preparedness and Response. This project has been funded in part by federal funds from the Military Infectious Disease Research Program Proposals MI210200 and MI220020. We thank L. Li (Metabolomics Center, Roy J. Carver Biotechnology Center, UIUC) for LC-MS/MS analysis. We thank Dean Olson, Lingyang Zhu, and N. Duay at the School of Chemical Sciences NMR Laboratory at UIUC for NMR services. The Bruker 500 MHz NMR spectrometer was obtained with the financial support of the Roy J. Carver Charitable Trust, Muscatine, Iowa.

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    The Infectious Diseases Society of America (IDSA) continues to view with concern the lean pipeline for novel therapeutics to treat drug-resistant infections, especially those caused by gram-negative pathogens. Infections now occur that are resistant to all current antibacterial options. Although the IDSA is encouraged by the prospect of success for some agents currently in preclinical development, there is an urgent, immediate need for new agents with activity against these panresistant organisms. There is no evidence that this need will be met in the foreseeable future. Furthermore, we remain concerned that the infrastructure for discovering and developing new antibacterials continues to stagnate, thereby risking the future pipeline of antibacterial drugs. The IDSA proposed solutions in its 2004 policy report, "Bad Bugs, No Drugs: As Antibiotic R&D Stagnates, a Public Health Crisis Brews," and recently issued a "Call to Action" to provide an update on the scope of the problem and the proposed solutions. A primary objective of these periodic reports is to encourage a community and legislative response to establish greater financial parity between the antimicrobial development and the development of other drugs. Although recent actions of the Food and Drug Administration and the 110th US Congress present a glimmer of hope, significant uncertainly remains. Now, more than ever, it is essential to create a robust and sustainable antibacterial research and development infrastructure--one that can respond to current antibacterial resistance now and anticipate evolving resistance. This challenge requires that industry, academia, the National Institutes of Health, the Food and Drug Administration, the Centers for Disease Control and Prevention, the US Department of Defense, and the new Biomedical Advanced Research and Development Authority at the Department of Health and Human Services work productively together. This report provides an update on potentially effective antibacterial drugs in the late-stage development pipeline, in the hope of encouraging such collaborative action.
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  7. 7
    Cassini, A.; Hogberg, L. D.; Plachouras, D.; Quattrocchi, A.; Hoxha, A.; Simonsen, G. S.; Colomb-Cotinat, M.; Kretzschmar, M. E.; Devleesschauwer, B.; Cecchini, M.; Ouakrim, D. A.; Oliveira, T. C.; Struelens, M. J.; Suetens, C.; Monnet, D. L.; the Burden of AMR Collective Group Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: a population-level modelling analysis. Lancet Infect. Dis. 2019, 19 (1), 56– 66,  DOI: 10.1016/S1473-3099(18)30605-4
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    7
    Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: a population-level modelling analysis
    Cassini Alessandro; Hogberg Liselotte Diaz; Plachouras Diamantis; Quattrocchi Annalisa; Hoxha Ana; Struelens Marc J; Suetens Carl; Monnet Dominique L; Simonsen Gunnar Skov; Colomb-Cotinat Melanie; Kretzschmar Mirjam E; Devleesschauwer Brecht; Cecchini Michele; Ouakrim Driss Ait; Oliveira Tiago Cravo
    The Lancet. Infectious diseases (2019), 19 (1), 56-66 ISSN:.
    BACKGROUND: Infections due to antibiotic-resistant bacteria are threatening modern health care. However, estimating their incidence, complications, and attributable mortality is challenging. We aimed to estimate the burden of infections caused by antibiotic-resistant bacteria of public health concern in countries of the EU and European Economic Area (EEA) in 2015, measured in number of cases, attributable deaths, and disability-adjusted life-years (DALYs). METHODS: We estimated the incidence of infections with 16 antibiotic resistance-bacterium combinations from European Antimicrobial Resistance Surveillance Network (EARS-Net) 2015 data that was country-corrected for population coverage. We multiplied the number of bloodstream infections (BSIs) by a conversion factor derived from the European Centre for Disease Prevention and Control point prevalence survey of health-care-associated infections in European acute care hospitals in 2011-12 to estimate the number of non-BSIs. We developed disease outcome models for five types of infection on the basis of systematic reviews of the literature. FINDINGS: From EARS-Net data collected between Jan 1, 2015, and Dec 31, 2015, we estimated 671 689 (95% uncertainty interval [UI] 583 148-763 966) infections with antibiotic-resistant bacteria, of which 63·5% (426 277 of 671 689) were associated with health care. These infections accounted for an estimated 33 110 (28 480-38 430) attributable deaths and 874 541 (768 837-989 068) DALYs. The burden for the EU and EEA was highest in infants (aged <1 year) and people aged 65 years or older, had increased since 2007, and was highest in Italy and Greece. INTERPRETATION: Our results present the health burden of five types of infection with antibiotic-resistant bacteria expressed, for the first time, in DALYs. The estimated burden of infections with antibiotic-resistant bacteria in the EU and EEA is substantial compared with that of other infectious diseases, and has increased since 2007. Our burden estimates provide useful information for public health decision-makers prioritising interventions for infectious diseases. FUNDING: European Centre for Disease Prevention and Control.
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    Antimicrobial Resistance, C. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet 2022, 399 (10325), 629– 655,  DOI: 10.1016/S0140-6736(21)02724-0
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    Richter, M. F.; Drown, B. S.; Riley, A. P.; Garcia, A.; Shirai, T.; Svec, R. L.; Hergenrother, P. J. Predictive compound accumulation rules yield a broad-spectrum antibiotic. Nature 2017, 545 (7654), 299– 304,  DOI: 10.1038/nature22308
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    Predictive compound accumulation rules yield a broad-spectrum antibiotic
    Richter, Michelle F.; Drown, Bryon S.; Riley, Andrew P.; Garcia, Alfredo; Shirai, Tomohiro; Svec, Riley L.; Hergenrother, Paul J.
    Nature (London, United Kingdom) (2017), 545 (7654), 299-304CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    Most small mols. are unable to rapidly traverse the outer membrane of Gram-neg. bacteria and accumulate inside these cells, making the discovery of much-needed drugs against these pathogens challenging. Current understanding of the physicochem. properties that dictate small-mol. accumulation in Gram-neg. bacteria is largely based on retrospective analyses of antibacterial agents, which suggest that polarity and mol. wt. are key factors. Here the authors assess the ability of over 180 diverse compds. to accumulate in Escherichia coli. Computational anal. of the results reveals major differences from the retrospective studies, namely that the small mols. that are most likely to accumulate contain an amine, are amphiphilic and rigid, and have low globularity. These guidelines were then applied to convert deoxynybomycin, a natural product that is active only against Gram-pos. organisms, into an antibiotic with activity against a diverse panel of multi-drug-resistant Gram-neg. pathogens. The authors anticipate that these findings will aid in the discovery and development of antibiotics against Gram-neg. bacteria.
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  10. 10
    Zhao, S.; Adamiak, J. W.; Bonifay, V.; Mehla, J.; Zgurskaya, H. I.; Tan, D. S. Defining new chemical space for drug penetration into Gram-negative bacteria. Nat. Chem. Biol. 2020, 16 (12), 1293– 1302,  DOI: 10.1038/s41589-020-00674-6
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    Defining new chemical space for drug penetration into Gram-negative bacteria
    Zhao, Shibin; Adamiak, Justyna W.; Bonifay, Vincent; Mehla, Jitender; Zgurskaya, Helen I.; Tan, Derek S.
    Nature Chemical Biology (2020), 16 (12), 1293-1302CODEN: NCBABT; ISSN:1552-4450. (Nature Research)
    Abstr.: We live in the era of antibiotic resistance, and this problem will progressively worsen if no new solns. emerge. In particular, Gram-neg. pathogens present both biol. and chem. challenges that hinder the discovery of new antibacterial drugs. First, these bacteria are protected from a variety of structurally diverse drugs by a low-permeability barrier composed of two membranes with distinct permeability properties, in addn. to active drug efflux, making this cell envelope impermeable to most compds. Second, chem. libraries currently used in drug discovery contain few compds. that can penetrate Gram-neg. bacteria. As a result of these challenges, intensive screening campaigns have led to few successes, highlighting the need for new approaches to identify regions of chem. space that are specifically relevant to antibacterial drug discovery. Herein we provide an overview of emerging insights into this problem and outline a general approach to addressing it using prospective anal. of chem. libraries for the ability of compds. to accumulate in Gram-neg. bacteria. The overall goal is to develop robust cheminformatic tools to predict Gram-neg. permeation and efflux, which can then be used to guide medicinal chem. campaigns and the design of antibacterial discovery libraries.
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  11. 11
    Munoz, K. A.; Hergenrother, P. J. Facilitating Compound Entry as a Means to Discover Antibiotics for Gram-Negative Bacteria. Acc. Chem. Res. 2021, 54 (6), 1322– 1333,  DOI: 10.1021/acs.accounts.0c00895
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    11
    Facilitating Compound Entry as a Means to Discover Antibiotics for Gram-Negative Bacteria
    Munoz, Kristen A.; Hergenrother, Paul J.
    Accounts of Chemical Research (2021), 54 (6), 1322-1333CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
    A review. It has been over half a century since the last class of antibiotics active against the most problematic Gram-neg. bacteria was approved by the Food and Drug Administration (FDA). The major challenge with developing antibiotics to treat these infections is not drug-target engagement but rather the inability of most small mols. to traverse the Gram-neg. membranes, be retained, and accumulate within the cell. Despite an abundance of lead compds., limited understanding of the physicochem. properties needed for compd. accumulation (or avoidance of efflux) in Gram-neg. bacteria has precluded a generalizable approach for developing Gram-neg. antibiotics. Indeed, in many instances, despite years of intensive derivatization efforts and the synthesis of hundreds of compds. aimed at building in Gram-neg. activity, little or no progress has been made in expanding the spectrum of activity for many Gram-pos.-only antibiotics. We describe the discovery and successful applications of a promising strategy for enhancing the accumulation of Gram-pos.-only antibiotics as a means of imbuing compds. with broad-spectrum activity. Utilizing a prospective approach examg. the accumulation in Escherichia coli for >180 diverse compds., we found that small mols. have an increased likelihood to accumulate in E. coli when they contain an ionizable nitrogen, have low 3-dimensionality, and are rigid. Implementing these guidelines, codified as the eNTRy rules and assisted by web application www.entry-way.org, we have facilitated compd. entry and systematically built Gram-neg. activity into Gram-pos.-only antibiotics. Though each antibiotic will have case-specific considerations, we describe a set of important criteria to consider when selecting candidate Gram-pos.-only antibiotics for conversion to Gram-neg.-active versions via the eNTRy rules. As detailed herein, using this blueprint the spectrum of activity was expanded for 3 antibiotic classes that engage 3 different biol. targets: DNA gyrase inhibitor 6DNM, FabI inhibitor Debio-1452, and FMN riboswitch inhibitor Ribocil C. In each scenario, the eNTRy rules guided the synthesis of key analogs predisposed to accumulate in Gram-neg. bacteria leading to compds. that display antibiotic activity (min. inhibitory concns. (MIC) ≤8μg/mL) against E. coli and other Gram-neg. ESKAPE pathogens. While the eNTRy rules will continue to be refined and enhanced as more accumulation data is gathered, on the basis of these collective results and on other examples not covered herein it is clear that the eNTRy rules are actionable for the development of novel broad-spectrum antibiotics from Gram-pos.-only compds. By enabling the prediction of compd. accumulation, the eNTRy rules should facilitate the process of discovering and developing novel antibiotics active against Gram-neg. bacteria.
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  12. 12
    Payne, D. J.; Gwynn, M. N.; Holmes, D. J.; Pompliano, D. L. Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat. Rev. Drug Discov 2007, 6 (1), 29– 40,  DOI: 10.1038/nrd2201
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    Drugs for bad bugs: confronting the challenges of antibacterial discovery
    Payne, David J.; Gwynn, Michael N.; Holmes, David J.; Pompliano, David L.
    Nature Reviews Drug Discovery (2007), 6 (1), 29-40CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
    A review. The sequencing of the first complete bacterial genome in 1995 heralded a new era of hope for antibacterial drug discoverers, who now had the tools to search entire genomes for new antibacterial targets. Several companies, including GlaxoSmithKline, moved back into the antibacterials area and embraced a genomics-derived, target-based approach to screen for new classes of drugs with novel modes of action. Here, we share our experience of evaluating more than 300 genes and 70 high-throughput screening campaigns over a period of 7 years, and look at what we learned and how that has influenced GlaxoSmithKline's antibacterials strategy going forward.
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    Tommasi, R.; Brown, D. G.; Walkup, G. K.; Manchester, J. I.; Miller, A. A. ESKAPEing the labyrinth of antibacterial discovery. Nat. Rev. Drug Discov 2015, 14 (8), 529– 42,  DOI: 10.1038/nrd4572
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    ESKAPEing the labyrinth of antibacterial discovery
    Tommasi, Ruben; Brown, Dean G.; Walkup, Grant K.; Manchester, John I.; Miller, Alita A.
    Nature Reviews Drug Discovery (2015), 14 (8), 529-542CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
    A review. Antimicrobial drug resistance is a growing threat to global public health. Multidrug resistance among the 'ESKAPE' organisms - encompassing Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp. - is of particular concern because they are responsible for many serious infections in hospitals. Although some promising agents are in the pipeline, there is an urgent need for new antibiotic scaffolds. However, antibacterial researchers have struggled to identify new small mols. with meaningful cellular activity, esp. those effective against multidrug-resistant Gram-neg. pathogens. This difficulty ultimately stems from an incomplete understanding of efflux systems and compd. permeation through bacterial membranes. This Opinion article describes findings from target-based and phenotypic screening efforts carried out at AstraZeneca over the past decade, discusses some of the subsequent chem. challenges and concludes with a description of new approaches comprising a combination of computational modeling and advanced biol. tools which may pave the way towards the discovery of new antibacterial agents.
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    Yao, J.; Rock, C. O. Resistance Mechanisms and the Future of Bacterial Enoyl-Acyl Carrier Protein Reductase (FabI) Antibiotics. Cold Spring Harb Perspect Med. 2016, 6 (3), a027045,  DOI: 10.1101/cshperspect.a027045
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    Seefeld, M. A.; Miller, W. H.; Newlander, K. A.; Burgess, W. J.; Payne, D. J.; Rittenhouse, S. F.; Moore, T. D.; DeWolf, W. E., Jr.; Keller, P. M.; Qiu, X.; Janson, C. A.; Vaidya, K.; Fosberry, A. P.; Smyth, M. G.; Jaworski, D. D.; Slater-Radosti, C.; Huffman, W. F. Inhibitors of bacterial enoyl acyl carrier protein reductase (FabI): 2,9-disubstituted 1,2,3,4-tetrahydropyrido[3,4-b]indoles as potential antibacterial agents. Bioorg. Med. Chem. Lett. 2001, 11 (17), 2241– 4,  DOI: 10.1016/S0960-894X(01)00405-X
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    Inhibitors of bacterial enoyl acyl carrier protein reductase (FabI): 2,9-disubstituted 1,2,3,4-tetrahydropyrido[3,4-b]indoles as potential antibacterial agents
    Seefeld, M. A.; Miller, W. H.; Newlander, K. A.; Burgess, W. J.; Payne, D. J.; Rittenhouse, S. F.; Moore, T. D.; DeWolf, W. E.; Keller, P. M.; Qiu, X.; Janson, C. A.; Vaidya, K.; Fosberry, A. P.; Smyth, M. G.; Jaworski, D. D.; Slater-Radosti, C.; Huffman, W. F.
    Bioorganic & Medicinal Chemistry Letters (2001), 11 (17), 2241-2244CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)
    An SAR study of a screening lead has led to the identification of 2,9-disubstituted 1,2,3,4-tetrahydropyrido[3,4-b]indoles as inhibitors of Staphylococcus aureus enoyl acyl carrier protein reductase (FabI).
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    Payne, D. J.; Miller, W. H.; Berry, V.; Brosky, J.; Burgess, W. J.; Chen, E.; DeWolf Jr, W. E., Jr.; Fosberry, A. P.; Greenwood, R.; Head, M. S.; Heerding, D. A.; Janson, C. A.; Jaworski, D. D.; Keller, P. M.; Manley, P. J.; Moore, T. D.; Newlander, K. A.; Pearson, S.; Polizzi, B. J.; Qiu, X.; Rittenhouse, S. F.; Slater-Radosti, C.; Salyers, K. L.; Seefeld, M. A.; Smyth, M. G.; Takata, D. T.; Uzinskas, I. N.; Vaidya, K.; Wallis, N. G.; Winram, S. B.; Yuan, C. C.; Huffman, W. F. Discovery of a novel and potent class of FabI-directed antibacterial agents. Antimicrob. Agents Chemother. 2002, 46 (10), 3118– 24,  DOI: 10.1128/AAC.46.10.3118-3124.2002
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    Discovery of a novel and potent class of FabI-directed antibacterial agents
    Payne, David J.; Miller, William H.; Berry, Valerie; Brosky, John; Burgess, Walter J.; Chen, Emile; DeWolf, Walter E., Jr.; Fosberry, Andrew P.; Greenwood, Rebecca; Head, Martha S.; Heerding, Dirk A.; Janson, Cheryl A.; Jaworski, Deborah D.; Keller, Paul M.; Manley, Peter J.; Moore, Terrance D.; Newlander, Kenneth A.; Pearson, Stewart; Polizzi, Brian J.; Qiu, Xiayang; Rittenhouse, Stephen F.; Slater-Radosti, Courtney; Salyers, Kevin L.; Seefeld, Mark A.; Smyth, Martin G.; Takata, Dennis T.; Uzinskas, Irene N.; Vaidya, Kalindi; Wallis, Nicola G.; Winram, Scott B.; Yuan, Catherine C. K.; Huffman, William F.
    Antimicrobial Agents and Chemotherapy (2002), 46 (10), 3118-3124CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
    Bacterial enoyl-acyl carrier protein (ACP) reductase (FabI) catalyzes the final step in each elongation cycle of bacterial fatty acid biosynthesis and is an attractive target for the development of new antibacterial agents. High-throughput screening of the Staphylococcus aureus FabI enzyme identified a novel, weak inhibitor with no detectable antibacterial activity against S. aureus. Iterative medicinal chem. and x-ray crystal structure-based design led to the identification of compd. 4 [(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide], which is 350-fold more potent than the original lead compd. obtained by high-throughput screening in the FabI inhibition assay. Compd. 4 has exquisite antistaphylococci activity, achieving MICs at which 90% of isolates are inhibited more than 500 times lower than those of nine currently available antibiotics against a panel of multidrug-resistant strains of S. aureus and Staphylococcus epidermidis. Furthermore, compd. 4 exhibits excellent in vivo efficacy in an S. aureus infection model in rats. Biochem. and genetic approaches have confirmed that the mode of antibacterial action of compd. 4 and related compd. is via inhibition of FabI. Compd. 4 also exhibits weak FabK inhibitory activity, which may explain its antibacterial activity against Streptococcus pneumoniae and Enterococcus faecalis, which depend on FabK and both FabK and FabI, resp., for their enoyl-ACP reductase function. These results show that compd. 4 is representative of a new, totally synthetic series of antibacterial agents that has the potential to provide novel alternatives for the treatment of S. aureus infections that are resistant to our present armory of antibiotics.
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    Wittke, F.; Vincent, C.; Chen, J.; Heller, B.; Kabler, H.; Overcash, J. S.; Leylavergne, F.; Dieppois, G. Afabicin, a First-in-Class Antistaphylococcal Antibiotic, in the Treatment of Acute Bacterial Skin and Skin Structure Infections: Clinical Noninferiority to Vancomycin/Linezolid. Antimicrob. Agents Chemother. 2020, 64 (10), e00250-20,  DOI: 10.1128/AAC.00250-20
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    Karlowsky, J. A.; Kaplan, N.; Hafkin, B.; Hoban, D. J.; Zhanel, G. G. AFN-1252, a FabI inhibitor, demonstrates a Staphylococcus-specific spectrum of activity. Antimicrob. Agents Chemother. 2009, 53 (8), 3544– 8,  DOI: 10.1128/AAC.00400-09
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    AFN-1252, a FabI inhibitor, demonstrates a staphylococcus-specific spectrum of activity
    Karlowsky, James A.; Kaplan, Nachum; Hafkin, Barry; Hoban, Daryl J.; Zhanel, George G.
    Antimicrobial Agents and Chemotherapy (2009), 53 (8), 3544-3548CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
    AFN-1252, a potent inhibitor of enoyl-acyl carrier protein reductase (FabI), inhibited all clin. isolates of Staphylococcus aureus (n = 502) and Staphylococcus epidermidis (n = 51) tested, including methicillin (methicillin)-resistant isolates, at concns. of ≤0.12 μg/mL. In contrast, AFN-1252 was inactive (MIC90, >4 μg/mL) against clin. isolates of Streptococcus pneumoniae, beta-hemolytic streptococci, Enterococcus spp., Enterobacteriaceae, nonfermentative gram-neg. bacilli, and Moraxella catarrhalis. These data support the continued development of AFN-1252 for the treatment of patients with resistant staphylococcal infections.
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    Parker, E. N.; Drown, B. S.; Geddes, E. J.; Lee, H. Y.; Ismail, N.; Lau, G. W.; Hergenrother, P. J. Implementation of permeation rules leads to a FabI inhibitor with activity against Gram-negative pathogens. Nat. Microbiol 2020, 5 (1), 67– 75,  DOI: 10.1038/s41564-019-0604-5
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    Implementation of permeation rules leads to a FabI inhibitor with activity against Gram-negative pathogens
    Parker, Erica N.; Drown, Bryon S.; Geddes, Emily J.; Lee, Hyang Yeon; Ismail, Nahed; Lau, Gee W.; Hergenrother, Paul J.
    Nature Microbiology (2020), 5 (1), 67-75CODEN: NMAICH; ISSN:2058-5276. (Nature Research)
    Gram-neg. bacterial infections are a significant public health concern, and the lack of new drug classes for these pathogens is linked to the inability of most drug leads to accumulate inside Gram-neg. bacteria1-7. Here, we report the development of a web application-eNTRyway-that predicts compd. accumulation (in Escherichia coli) from its structure. In conjunction with structure-activity relationships and X-ray data, eNTRyway was utilized to re-design Debio-1452-a Gram-pos.-only antibiotic8-into versions that accumulate in E. coli and possess antibacterial activity against high-priority Gram-neg. pathogens. The lead compd. Debio-1452-NH3 operates as an antibiotic via the same mechanism as Debio-1452, namely potent inhibition of the enoyl-acyl carrier protein reductase FabI, as validated by in vitro enzyme assays and the generation of bacterial isolates with spontaneous target mutations. Debio-1452-NH3 is well tolerated in vivo, reduces bacterial burden in mice and rescues mice from lethal infections with clin. isolates of Acinetobacter baumannii, Klebsiella pneumoniae and E. coli. This work provides tools for the facile discovery and development of high-accumulating compds. in E. coli, and a general blueprint for the conversion of Gram-pos.-only compds. into broad-spectrum antibiotics.
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    Richter, M. F.; Hergenrother, P. J. The challenge of converting Gram-positive-only compounds into broad-spectrum antibiotics. Ann. N.Y. Acad. Sci. 2019, 1435 (1), 18– 38,  DOI: 10.1111/nyas.13598
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    The challenge of converting Gram-positive-only compounds into broad-spectrum antibiotics
    Richter, Michelle F.; Hergenrother, Paul J.
    Annals of the New York Academy of Sciences (2019), 1435 (1, Antimicrobial Therapeutics Reviews), 18-38CODEN: ANYAA9; ISSN:0077-8923. (John Wiley & Sons, Inc.)
    A review. Multidrug resistant Gram-neg. bacterial infections are on the rise, and there is a lack of new classes of drugs to treat these pathogens. This drug shortage is largely due to the challenge of finding antibiotics that can permeate and persist inside Gram-neg. species. Efforts to understand the mol. properties that enable certain compds. to accumulate in Gram-neg. bacteria based on retrospective studies of known antibiotics have not been generally actionable in the development of new antibiotics. A recent assessment of the ability of >180 diverse small mols. to accumulate in Escherichia coli led to predictive guidelines for compd. accumulation in E. coli. These "eNTRy rules" state that compds. are most likely to accumulate if they contain a nonsterically encumbered ionizable Nitrogen (primary amines are the best), have low Three-dimensionality (globularity ≤ 0.25), and are relatively Rigid (rotatable bonds ≤ 5). In this review, we look back through 50+ years of antibacterial research and 1000s of derivs. and assess this historical data set through the lens of these predictive guidelines. The results are consistent with the eNTRy rules, suggesting that the eNTRy rules may provide an actionable and general roadmap for the conversion of Gram-pos.-only compds. into broad-spectrum antibiotics.
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    Kaplan, N.; Albert, M.; Awrey, D.; Bardouniotis, E.; Berman, J.; Clarke, T.; Dorsey, M.; Hafkin, B.; Ramnauth, J.; Romanov, V.; Schmid, M. B.; Thalakada, R.; Yethon, J.; Pauls, H. W. Mode of action, in vitro activity, and in vivo efficacy of AFN-1252, a selective antistaphylococcal FabI inhibitor. Antimicrob. Agents Chemother. 2012, 56 (11), 5865– 5874,  DOI: 10.1128/AAC.01411-12
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    21
    Mode of action, in vitro activity, and in vivo efficacy of AFN-1252, a selective antistaphylococcal FabI inhibitor
    Kaplan, Nachum; Albert, Monique; Awrey, Donald; Bardouniotis, Elias; Berman, Judd; Clarke, Teresa; Dorsey, Mandy; Hafkin, Barry; Ramnauth, Jaillal; Romanov, Vladimir; Schmid, Molly B.; Thalakada, Rosanne; Yethon, Jeremy; Pauls, Henry W.
    Antimicrobial Agents and Chemotherapy (2012), 56 (11), 5865-5874CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
    The mechanism of action of AFN-1252, a selective inhibitor of Staphylococcus aureus enoyl-acyl carrier protein reductase (FabI), which is involved in fatty acid biosynthesis, was confirmed by using biochem., macromol. synthesis, genetics, and co-crystn. of an AFN-1252-FabI complex. AFN-1252 demonstrated a low propensity for spontaneous resistance development and a time-dependent redn. of the viability of both methicillin-susceptible and methicillin-resistant S. aureus, achieving a ≥2-log10 redn. in S. aureus counts over 24 h, and was extremely potent against clin. isolates of S. aureus (MIC90, 0.015 μg/mL) and coagulase-neg. staphylococci (MIC90, 0.12 μg/mL), regardless of their drug resistance, hospital- or community-assocd. origin, or other clin. subgroup. AFN-1252 was orally available in mouse pharmacokinetic studies, and a single oral dose of 1 mg/kg AFN-1252 was efficacious in a mouse model of septicemia, providing 100% protection from an otherwise lethal peritoneal infection of S. aureus Smith. A median ED of 0.15 mg/kg indicated that AFN-1252 was 12 to 24 times more potent than linezolid in the model. These studies, demonstrating a selective mode of action, potent in vitro activity, and in vivo efficacy, support the continued investigation of AFN-1252 as a targeted therapeutic for staphylococcal infections.
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  22. 22
    Seefeld, M. A.; Miller, W. H.; Newlander, K. A.; Burgess, W. J.; DeWolf, W. E., Jr.; Elkins, P. A.; Head, M. S.; Jakas, D. R.; Janson, C. A.; Keller, P. M.; Manley, P. J.; Moore, T. D.; Payne, D. J.; Pearson, S.; Polizzi, B. J.; Qiu, X.; Rittenhouse, S. F.; Uzinskas, I. N.; Wallis, N. G.; Huffman, W. F. Indole naphthyridinones as inhibitors of bacterial enoyl-ACP reductases FabI and FabK. J. Med. Chem. 2003, 46 (9), 1627– 35,  DOI: 10.1021/jm0204035
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    22
    Indole Naphthyridinones as Inhibitors of Bacterial Enoyl-ACP Reductases FabI and FabK
    Seefeld, Mark A.; Miller, William H.; Newlander, Kenneth A.; Burgess, Walter J.; DeWolf, Walter E., Jr.; Elkins, Patricia A.; Head, Martha S.; Jakas, Dalia R.; Janson, Cheryl A.; Keller, Paul M.; Manley, Peter J.; Moore, Terrance D.; Payne, David J.; Pearson, Stewart; Polizzi, Brian J.; Qiu, Xiayang; Rittenhouse, Stephen F.; Uzinskas, Irene N.; Wallis, Nicola G.; Huffman, William F.
    Journal of Medicinal Chemistry (2003), 46 (9), 1627-1635CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Bacterial enoyl-ACP reductase (FabI) is responsible for catalyzing the final step of bacterial fatty acid biosynthesis and is an attractive target for the development of novel antibacterial agents. Previously we reported the development of FabI inhibitor 4 with narrow spectrum antimicrobial activity and in vivo efficacy against Staphylococcus aureus via i.p. administration. Through iterative medicinal chem. aided by x-ray crystal structure anal., a new series of inhibitors has been developed with greatly increased potency against FabI-contg. organisms. Several of these new inhibitors have potent antibacterial activity against multidrug resistant strains of S. aureus, and compd. 30 demonstrates exceptional oral (po) in vivo efficacy in a S. aureus infection model in rats. While optimizing FabI inhibitory activity, compds. 29 and 30 were identified as having low micromolar FabK inhibitory activity, thereby increasing the antimicrobial spectrum of these compds. to include the FabK-contg. pathogens Streptococcus pneumoniae and Enterococcus faecalis. The results described herein support the hypothesis that bacterial enoyl-ACP reductases are valid targets for antibacterial agents.
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  23. 23
    Ramnauth, J.; Surman, M. D.; Sampson, P. B.; Forrest, B.; Wilson, J.; Freeman, E.; Manning, D. D.; Martin, F.; Toro, A.; Domagala, M.; Awrey, D. E.; Bardouniotis, E.; Kaplan, N.; Berman, J.; Pauls, H. W. 2,3,4,5-Tetrahydro-1H-pyrido[2,3-b and e][1,4]diazepines as inhibitors of the bacterial enoyl ACP reductase, FabI. Bioorg. Med. Chem. Lett. 2009, 19 (18), 5359– 5362,  DOI: 10.1016/j.bmcl.2009.07.094
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    23
    2,3,4,5-Tetrahydro-1H-pyrido[2,3-b and e][1,4]diazepines as inhibitors of the bacterial enoyl ACP reductase, FabI
    Ramnauth, Jailall; Surman, Mathew D.; Sampson, Peter B.; Forrest, Bryan; Wilson, Jeff; Freeman, Emily; Manning, David D.; Martin, Fernando; Toro, Andras; Domagala, Megan; Awrey, Donald E.; Bardouniotis, Elias; Kaplan, Nachum; Berman, Judd; Pauls, Henry W.
    Bioorganic & Medicinal Chemistry Letters (2009), 19 (18), 5359-5362CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    In the search for new antibacterial agents, the enzyme FabI has been identified as an attractive target. Employing a structure guided approach, the previously reported ene-amide series of FabI inhibitors were expanded to include 2,3,4,5-tetrahydro-1H-pyrido[2,3-b and e][1,4]diazepines, e.g. I (R = 1-methyl-2-indolyl, 3-methyl-2-benzofuranyl, etc.; X = H2, O) and II. These novel series incorporate addnl. H-bonding functions and can be more water sol. than their naphthyridinone progenitors; diazepine II (R = 1-methyl-2-indolyl; X = O) is shown to be efficacious in a mouse infection model.
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  24. 24
    Takhi, M.; Sreenivas, K.; Reddy, C. K.; Munikumar, M.; Praveena, K.; Sudheer, P.; Rao, B. N.; Ramakanth, G.; Sivaranjani, J.; Mulik, S.; Reddy, Y. R.; Narasimha Rao, K.; Pallavi, R.; Lakshminarasimhan, A.; Panigrahi, S. K.; Antony, T.; Abdullah, I.; Lee, Y. K.; Ramachandra, M.; Yusof, R.; Rahman, N. A.; Subramanya, H. Discovery of azetidine based ene-amides as potent bacterial enoyl ACP reductase (FabI) inhibitors. Eur. J. Med. Chem. 2014, 84, 382– 394,  DOI: 10.1016/j.ejmech.2014.07.036
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    24
    Discovery of azetidine based ene-amides as potent bacterial enoyl ACP reductase (FabI) inhibitors
    Takhi, Mohamed; Sreenivas, Kandepu; Reddy, Chandrashekar K.; Munikumar, Mahadari; Praveena, Kolakota; Sudheer, Pabolu; Rao, Bandaru N. V. M.; Ramakanth, Gollamudi; Sivaranjani, Jampala; Mulik, Shardaprasad; Reddy, Yeruva R.; Narasimha Rao, Krishnamurthy; Pallavi, Rentala; Lakshminarasimhan, Anirudha; Panigrahi, Sunil K.; Antony, Thomas; Abdullah, Iskandar; Lee, Yean K.; Ramachandra, Murali; Yusof, Rohana; Rahman, Noorsaadah A.; Subramanya, Hosahalli
    European Journal of Medicinal Chemistry (2014), 84 (), 382-394CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
    A novel and potent series of ene-amides featuring azetidines has been developed as FabI inhibitors active against drug resistant Gram-pos. pathogens particularly staphylococcal organisms. Most of the compds. from the series possessed excellent biochem. inhibition of Staphylococcus aureus FabI enzyme and whole cell activity against clin. relevant MRSA, MSSA and MRSE organisms which are responsible for significant morbidity and mortality in community as well as hospital settings. The binding mode of one of the leads, I, in Escherichia coli FabI enzyme was detd. unambiguously using x-ray crystallog. The lead compds. displayed good metabolic stability in mice liver microsomes and pharmacokinetic profile in mice. The in vivo efficacy of lead AEA16 has been demonstrated in a lethal murine systemic infection model.
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  25. 25
    Hergenrother, P. J.; Geddes, E. J.; Drown, B. S.; Motika, S. E.; Parker, S. E. Antibiotics Effective for Gram-Negative Pathogens. WO2019/177975A1, 2019.
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    Gerusz, V. B.; Bravo, J.; Pauls, H.; Berman, J.; Finn, T. Novel Compounds and their Use. WO2021/123372A1, 2021.
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    There is no corresponding record for this reference.
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    Hergenrother, P. J.; Parker, E. N.; Hung, D.; Serrano-Wu, M.; Lee, K. K. FabI inhibitors for Gram-negative pathogens. US Provisional Patent Application No. 63/156,145. 2021.
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    There is no corresponding record for this reference.
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    Geddes, E. J.; Li, Z.; Hergenrother, P. J. An LC-MS/MS assay and complementary web-based tool to quantify and predict compound accumulation in E. coli. Nat. Protoc 2021, 16 (10), 4833– 4854,  DOI: 10.1038/s41596-021-00598-y
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    27
    An LC-MS/MS assay and complementary web-based tool to quantify and predict compound accumulation in E. coli
    Geddes, Emily J.; Li, Zhong; Hergenrother, Paul J.
    Nature Protocols (2021), 16 (10), 4833-4854CODEN: NPARDW; ISSN:1750-2799. (Nature Portfolio)
    A review. Novel classes of broad-spectrum antibiotics have been extremely difficult to discover, largely due to the impermeability of the Gram-neg. membranes coupled with a poor understanding of the physicochem. properties a compd. should possess to promote its accumulation inside the cell. To address this challenge, numerous methodologies for assessing intracellular compd. accumulation in Gram-neg. bacteria have been established, including classic radiometric and fluorescence-based methods. The recent development of accumulation assays that utilize liq. chromatog.-tandem mass spectrometry (LC-MS/MS) have circumvented the requirement for labeled compds., enabling assessment of a substantially broader range of small mols. Our unbiased study of accumulation trends in Escherichia coli using an LC-MS/MS-based assay led to the development of the eNTRy rules, which stipulate that a compd. is most likely to accumulate in E. coli if it has an ionizable Nitrogen, has low Three-dimensionality and is relatively Rigid. To aid in the implementation of the eNTRy rules, we developed a complementary web tool, eNTRyway, which calcs. relevant properties and predicts compd. accumulation. Here we provide a comprehensive protocol for anal. and prediction of intracellular accumulation of small mols. in E. coli using an LC-MS/MS-based assay (which takes ∼2 d) and eNTRyway, a workflow that is readily adoptable by any microbiol., biochem. or chem. biol. lab.
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  29. 29
    Zhu, L.; Lin, J.; Ma, J.; Cronan, J. E.; Wang, H. Triclosan resistance of Pseudomonas aeruginosa PAO1 is due to FabV, a triclosan-resistant enoyl-acyl carrier protein reductase. Antimicrob. Agents Chemother. 2010, 54 (2), 689– 698,  DOI: 10.1128/AAC.01152-09
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    28
    Triclosan resistance of Pseudomonas aeruginosa PAO1 is due to FabV, a triclosan-resistant enoyl-acyl carrier protein reductase
    Zhu, Lei; Lin, Jinshui; Ma, Jincheng; Cronan, John E.; Wang, Haihong
    Antimicrobial Agents and Chemotherapy (2010), 54 (2), 689-698CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
    Triclosan, a very widely used biocide, specifically inhibits fatty acid synthesis by inhibition of enoyl-acyl carrier protein (ACP) reductase. Escherichia coli FabI is the prototypical triclosan-sensitive enoyl-ACP reductase, and E. coli is extremely sensitive to the biocide. However, other bacteria are resistant to triclosan, because they encode triclosan-resistant enoyl-ACP reductase isoenzymes. In contrast, the triclosan resistance of Pseudomonas aeruginosa PAO1 has been attributed to active efflux of the compd. We report that P. aeruginosa contains two enoyl-ACP reductase isoenzymes, the previously characterized FabI homolog plus a homolog of FabV, a triclosan-resistant enoyl-ACP reductase recently demonstrated in Vibrio cholerae. By deletion of the genes encoding P. aeruginosa FabI and FabV, we demonstrated that FabV confers triclosan resistance on P. aeruginosa. Upon deletion of the fabV gene, the mutant strain became extremely sensitive to triclosan (>2,000-fold more sensitive than the wild-type strain), whereas the mutant strain lacking FabI remained completely resistant to the biocide.
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  30. 30
    Parsons, J. B.; Frank, M. W.; Subramanian, C.; Saenkham, P.; Rock, C. O. Metabolic basis for the differential susceptibility of Gram-positive pathogens to fatty acid synthesis inhibitors. Proc. Natl. Acad. Sci. U. S. A. 2011, 108 (37), 15378– 15383,  DOI: 10.1073/pnas.1109208108
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    29
    Metabolic basis for the differential susceptibility of gram-positive pathogens to fatty acid synthesis inhibitors
    Parsons, Joshua B.; Frank, Matthew W.; Subramanian, Chitra; Saenkham, Panatda; Rock, Charles O.
    Proceedings of the National Academy of Sciences of the United States of America (2011), 108 (37), 15378-15383, S15378/1-S15378/10CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    The rationale for the pursuit of bacterial type 2 fatty acid synthesis (FASII) as a target for antibacterial drug discovery in Gram-pos. organisms is being debated vigorously based on their ability to incorporate extracellular fatty acids. The regulation of FASII by extracellular fatty acids was examd. in Staphylococcus aureus and Streptococcus pneumoniae, representing two important groups of pathogens. Both bacteria use the same enzymic tool kit for the conversion of extracellular fatty acids to acyl-acyl carrier protein, elongation, and incorporation into phospholipids. Exogenous fatty acids completely replace the endogenous fatty acids in S. pneumoniae but support only 50% of phospholipid synthesis in S. aureus. Fatty acids overcame FASII inhibition in S. pneumoniae but not in S. aureus. Extracellular fatty acids strongly suppress malonyl-CoA levels in S. pneumoniae but not in S. aureus, showing a feedback regulatory system in S. pneumoniae that is absent in S. aureus. Fatty acids overcame either a biochem. or a genetic block at acetyl-CoA carboxylase (ACC) in S. aureus, confirming that regulation at the ACC step is the key difference between these two species. Bacteria that possess a stringent biochem. feedback inhibition of ACC and malonyl-CoA formation triggered by environmental fatty acids are able to circumvent FASII inhibition. However, if exogenous fatty acids do not suppress malonyl-CoA formation, FASII inhibitors remain effective in the presence of fatty acid supplements.
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  31. 31
    Zhu, L.; Bi, H.; Ma, J.; Hu, Z.; Zhang, W.; Cronan, J. E.; Wang, H. The two functional enoyl-acyl carrier protein reductases of Enterococcus faecalis do not mediate triclosan resistance. mBio 2013, 4 (5), e00613– 13,  DOI: 10.1128/mBio.00613-13
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    30
    The two functional enoyl-acyl carrier protein reductases of Enterococcus faecalis do not mediate triclosan resistance
    Zhu, Lei; Bi, Hongkai; Ma, Jincheng; Hu, Zhe; Zhang, Wenbin; Cronan, John E.; Wang, Haihong
    mBio (2013), 4 (5), e00613/1-e00613/11CODEN: MBIOCL; ISSN:2150-7511. (American Society for Microbiology)
    Enoyl-acyl carrier protein (enoyl-ACP) reductase catalyzes the last step of the elongation cycle in the synthesis of bacterial fatty acids. The Enterococcus faecalis genome contains two genes annotated as enoyl-ACP reductases, a FabI-type enoyl- ACP reductase and a FabK-type enoyl-ACP reductase. The authors report that expression of either of the two proteins restores growth of an Escherichia coli fabI temp.-sensitive mutant strain under nonpermissive conditions. In vitro assays demonstrated that both proteins support fatty acid synthesis and are active with substrates of all fatty acid chain lengths. Although expression of E. faecalis fabK confers to E. coli high levels of resistance to the antimicrobial triclosan, deletion of fabK from the E. faecalis genome showed that FabK does not play a detectable role in the inherent triclosan resistance of E. faecalis. Indeed, FabK seems to play only a minor role in modulating fatty acid compn. Strains carrying a deletion of fabK grow normally without fatty acid supplementation, whereas fabI deletion mutants make only traces of fatty acids and are unsatd. fatty acid auxotrophs.
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  32. 32
    Yao, J.; Carter, R. A.; Vuagniaux, G.; Barbier, M.; Rosch, J. W.; Rock, C. O. A Pathogen-Selective Antibiotic Minimizes Disturbance to the Microbiome. Antimicrob. Agents Chemother. 2016, 60 (7), 4264– 73,  DOI: 10.1128/AAC.00535-16
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    31
    A pathogen-selective antibiotic minimizes disturbance to the microbiome
    Yao, Jiangwei; Carter, Robert A.; Vuagniaux, Gregoire; Barbier, Maryse; Rosch, Jason W.; Rock, Charles O.
    Antimicrobial Agents and Chemotherapy (2016), 60 (7), 4264-4273CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
    Broad-spectrum antibiotic therapy decimates the gut microbiome, resulting in a variety of neg. health consequences. Debio 1452 is a staphylococcus-selective enoyl-acyl carrier protein reductase (FabI) inhibitor under clin. development and was used to det. whether treatment with pathogen-selective antibiotics would minimize disturbance to the microbiome. The effect of oral Debio 1452 on the microbiota of mice was compared to the effects of four commonly used broad-spectrum oral antibiotics. During the 10 days of oral Debio 1452 treatment, there was minimal disturbance to the gut bacterial abundance and compn., with only the unclassified S24-7 taxon reduced at days 6 and 10. In comparison, broad-spectrum oral antibiotics caused ∼100- to 4000-fold decreases in gut bacterial abundance and severely altered the microbial compn. The gut bacterial abundance and compn. of Debio 1452-treated mice were indistinguishable from those of untreated mice 2 days after the antibiotic treatment was stopped. In contrast, the bacterial abundance in broad-spectrum-antibiotic-treated mice took up to 7 days to recover, and the gut compn. of the broad-spectrum-antibiotic-treated mice remained different from that of the control group 20 days after the cessation of antibiotic treatment. These results illustrate that a pathogen-selective approach to antibiotic development will minimize disturbance to the gut microbiome.
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  33. 33
    Imai, Y.; Meyer, K. J.; Iinishi, A.; Favre-Godal, Q.; Green, R.; Manuse, S.; Caboni, M.; Mori, M.; Niles, S.; Ghiglieri, M.; Honrao, C.; Ma, X.; Guo, J. J.; Makriyannis, A.; Linares-Otoya, L.; Bohringer, N.; Wuisan, Z. G.; Kaur, H.; Wu, R.; Mateus, A.; Typas, A.; Savitski, M. M.; Espinoza, J. L.; O’Rourke, A.; Nelson, K. E.; Hiller, S.; Noinaj, N.; Schaberle, T. F.; D’Onofrio, A.; Lewis, K. A new antibiotic selectively kills Gram-negative pathogens. Nature 2019, 576 (7787), 459– 464,  DOI: 10.1038/s41586-019-1791-1
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    A new antibiotic selectively kills Gram-negative pathogens
    Imai, Yu; Meyer, Kirsten J.; Iinishi, Akira; Favre-Godal, Quentin; Green, Robert; Manuse, Sylvie; Caboni, Mariaelena; Mori, Miho; Niles, Samantha; Ghiglieri, Meghan; Honrao, Chandrashekhar; Ma, Xiaoyu; Guo, Jason J.; Makriyannis, Alexandros; Linares-Otoya, Luis; Bohringer, Nils; Wuisan, Zerlina G.; Kaur, Hundeep; Wu, Runrun; Mateus, Andre; Typas, Athanasios; Savitski, Mikhail M.; Espinoza, Josh L.; O'Rourke, Aubrie; Nelson, Karen E.; Hiller, Sebastian; Noinaj, Nicholas; Schaberle, Till F.; D'Onofrio, Anthony; Lewis, Kim
    Nature (London, United Kingdom) (2019), 576 (7787), 459-464CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
    The current need for novel antibiotics is esp. acute for drug-resistant Gram-neg. pathogens1,2. These microorganisms have a highly restrictive permeability barrier, which limits the penetration of most compds.3,4. As a result, the last class of antibiotics that acted against Gram-neg. bacteria was developed in the 1960s2. We reason that useful compds. can be found in bacteria that share similar requirements for antibiotics with humans, and focus on Photorhabdus symbionts of entomopathogenic nematode microbiomes. Here we report a new antibiotic that we name darobactin, which was obtained using a screen of Photorhabdus isolates. Darobactin is coded by a silent operon with little prodn. under lab. conditions, and is ribosomally synthesized. Darobactin has an unusual structure with two fused rings that form post-translationally. The compd. is active against important Gram-neg. pathogens both in vitro and in animal models of infection. Mutants that are resistant to darobactin map to BamA, an essential chaperone and translocator that folds outer membrane proteins. Our study suggests that bacterial symbionts of animals contain antibiotics that are particularly suitable for development into therapeutics.
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  34. 34
    Leimer, N.; Wu, X.; Imai, Y.; Morrissette, M.; Pitt, N.; Favre-Godal, Q.; Iinishi, A.; Jain, S.; Caboni, M.; Leus, I. V.; Bonifay, V.; Niles, S.; Bargabos, R.; Ghiglieri, M.; Corsetti, R.; Krumpoch, M.; Fox, G.; Son, S.; Klepacki, D.; Polikanov, Y. S.; Freliech, C. A.; McCarthy, J. E.; Edmondson, D. G.; Norris, S. J.; D’Onofrio, A.; Hu, L. T.; Zgurskaya, H. I.; Lewis, K. A selective antibiotic for Lyme disease. Cell 2021, 184 (21), 5405– 5418,  DOI: 10.1016/j.cell.2021.09.011
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    33
    A selective antibiotic for Lyme disease
    Leimer, Nadja; Wu, Xiaoqian; Imai, Yu; Morrissette, Madeleine; Pitt, Norman; Favre-Godal, Quentin; Iinishi, Akira; Jain, Samta; Caboni, Mariaelena; Leus, Inga V.; Bonifay, Vincent; Niles, Samantha; Bargabos, Rachel; Ghiglieri, Meghan; Corsetti, Rachel; Krumpoch, Megan; Fox, Gabriel; Son, Sangkeun; Klepacki, Dorota; Polikanov, Yury S.; Freliech, Cecily A.; McCarthy, Julie E.; Edmondson, Diane G.; Norris, Steven J.; D'Onofrio, Anthony; Hu, Linden T.; Zgurskaya, Helen I.; Lewis, Kim
    Cell (Cambridge, MA, United States) (2021), 184 (21), 5405-5418.e16CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
    Lyme disease is on the rise. Caused by a spirochete Borreliella burgdorferi, it affects an estd. 500,000 people in the United States alone. The antibiotics currently used to treat Lyme disease are broad spectrum, damage the microbiome, and select for resistance in non-target bacteria. We therefore sought to identify a compd. acting selectively against B. burgdorferi. A screen of soil micro-organisms revealed a compd. highly selective against spirochetes, including B. burgdorferi. Unexpectedly, this compd. was detd. to be hygromycin A, a known antimicrobial produced by Streptomyces hygroscopicus. Hygromycin A targets the ribosomes and is taken up by B. burgdorferi, explaining its selectivity. Hygromycin A cleared the B. burgdorferi infection in mice, including animals that ingested the compd. in a bait, and was less disruptive to the fecal microbiome than clin. relevant antibiotics. This selective antibiotic holds the promise of providing a better therapeutic for Lyme disease and eradicating it in the environment.
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  35. 35
    Poyet, M.; Groussin, M.; Gibbons, S. M.; Avila-Pacheco, J.; Jiang, X.; Kearney, S. M.; Perrotta, A. R.; Berdy, B.; Zhao, S.; Lieberman, T. D.; Swanson, P. K.; Smith, M.; Roesemann, S.; Alexander, J. E.; Rich, S. A.; Livny, J.; Vlamakis, H.; Clish, C.; Bullock, K.; Deik, A.; Scott, J.; Pierce, K. A.; Xavier, R. J.; Alm, E. J. A library of human gut bacterial isolates paired with longitudinal multiomics data enables mechanistic microbiome research. Nat. Med. 2019, 25 (9), 1442– 1452,  DOI: 10.1038/s41591-019-0559-3
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    A library of human gut bacterial isolates paired with longitudinal multiomics data enables mechanistic microbiome research
    Poyet, M.; Groussin, M.; Gibbons, S. M.; Avila-Pacheco, J.; Jiang, X.; Kearney, S. M.; Perrotta, A. R.; Berdy, B.; Zhao, S.; Lieberman, T. D.; Swanson, P. K.; Smith, M.; Roesemann, S.; Alexander, J. E.; Rich, S. A.; Livny, J.; Vlamakis, H.; Clish, C.; Bullock, K.; Deik, A.; Scott, J.; Pierce, K. A.; Xavier, R. J.; Alm, E. J.
    Nature Medicine (New York, NY, United States) (2019), 25 (9), 1442-1452CODEN: NAMEFI; ISSN:1078-8956. (Nature Research)
    Our understanding of how the gut microbiome interacts with its human host has been restrained by limited access to longitudinal datasets to examine stability and dynamics, and by having only a few isolates to test mechanistic hypotheses. Here, we present the Broad Institute-OpenBiome Microbiome Library (BIO-ML), a comprehensive collection of 7,758 gut bacterial isolates paired with 3,632 genome sequences and longitudinal multi-omics data. We show that microbial species maintain stable population sizes within and across humans and that commonly used 'omics' survey methods are more reliable when using avs. over multiple days of sampling. Variation of gut metabolites within people over time is assocd. with amino acid levels, and differences across people are assocd. with differences in bile acids. Finally, we show that genomic diversification can be used to infer eco-evolutionary dynamics and in vivo selection pressures for strains within individuals. The BIO-ML is a unique resource designed to enable hypothesis-driven microbiome research.
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  36. 36
    Marrakchi, H.; Dewolf, W. E., Jr.; Quinn, C.; West, J.; Polizzi, B. J.; So, C. Y.; Holmes, D. J.; Reed, S. L.; Heath, R. J.; Payne, D. J.; Rock, C. O.; Wallis, N. G. Characterization of Streptococcus pneumoniae enoyl-(acyl-carrier protein) reductase (FabK). Biochem. J. 2003, 370 (3), 1055– 1062,  DOI: 10.1042/bj20021699
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    Characterization of Streptococcus pneumoniae enoyl-(acyl-carrier protein) reductase (FabK)
    Marrakchi, Hedia; Dewolf, Walter E., Jr.; Quinn, Chad; West, Joshua; Polizzi, Brian J.; So, Chi Y.; Holmes, David J.; Reed, Shannon L.; Heath, Richard J.; Payne, David J.; Rock, Charles O.; Wallis, Nicola G.
    Biochemical Journal (2003), 370 (3), 1055-1062CODEN: BIJOAK; ISSN:0264-6021. (Portland Press Ltd.)
    The enoyl-(acyl-carrier protein) (ACP) reductase catalyzes the last step in each cycle of fatty acid elongation in the type II fatty acid synthase systems. An extensively characterized NADH-dependent reductase, FabI, is widely distributed in bacteria and plants, whereas the enoyl-ACP reductase, FabK, is a distinctly different member of this enzyme group discovered in Streptococcus pneumoniae . We were unable to delete the fabK gene from Strep. pneumoniae , suggesting that this is the only enoyl-ACP reductase in this organism. The FabK enzyme was purified and the biochem. properties of the reductase were examd. The visible absorption spectrum of the purified protein indicated the presence of a flavin cofactor that was identified as FMN by MS, and was present in a 1:1 molar ratio with protein. FabK specifically required NADH and the protein activity was stimulated by ammonium ions. FabK also exhibited NADH oxidase activity in the absence of substrate. Strep. pneumoniae belongs to the Bacillus/Lactobacillus/Streptococcus group that includes Staphylococcus aureus and Bacillus subtilis . These two organisms also contain FabK-related genes, suggesting that they may also express a FabK-like enoyl-ACP reductase. However, the genes did not complement a fabI (Ts) mutant and the purified flavoproteins were unable to reduce enoyl-ACP in vitro and did not exhibit NAD(P)H oxidase activity, indicating they were not enoyl-ACP reductases. The restricted occurrence of the FabK enoyl-ACP reductase may be related to the role of substrate-independent NADH oxidn. in oxygen-dependent anaerobic energy metab.
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    An efficient asymmetric synthesis of (R)-3-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one
    Armstrong, Joseph D., III; Eng, Kan K.; Keller, Jennifer L.; Purick, Robert M.; Hartner, Frederick W., Jr.; Choi, Woo-Baeg; Askin, David; Volante, R. P.
    Tetrahedron Letters (1994), 35 (20), 3239-42CODEN: TELEAY; ISSN:0040-4039.
    Two approaches for the asym. prepn. of (-)- or (+)-α-aminobenzlactam I are described. One route is based on the asym. hydrogenation of enamide II and the other on the racemization/resoln. of (±)-I.
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    Galac, M. R.; Snesrud, E.; Lebreton, F.; Stam, J.; Julius, M.; Ong, A. C.; Maybank, R.; Jones, A. R.; Kwak, Y. I.; Hinkle, K.; Waterman, P. E.; Lesho, E. P.; Bennett, J. W.; Mc Gann, P. A Diverse Panel of Clinical Acinetobacter baumannii for Research and Development. Antimicrob. Agents Chemother. 2020, 64 (10), e00840-20,  DOI: 10.1128/AAC.00840-20
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    Rao, N. K.; Nataraj, V.; Ravi, M.; Panchariya, L.; Palai, K.; Talapati, S. R.; Lakshminarasimhan, A.; Ramachandra, M.; Antony, T. Ternary complex formation of AFN-1252 with Acinetobacter baumannii FabI and NADH: Crystallographic and biochemical studies. Chem. Biol. Drug Des 2020, 96 (2), 704– 713,  DOI: 10.1111/cbdd.13686
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    Ternary complex formation of AFN-1252 with Acinetobacter baumannii FabI and NADH: Crystallographic and biochemical studies
    Rao, Narasimha K.; Nataraj, Vijayashankar; Ravi, Mohan; Panchariya, Love; Palai, Kirttija; Talapati, Sumalatha R.; Lakshminarasimhan, Anirudha; Ramachandra, Murali; Antony, Thomas
    Chemical Biology & Drug Design (2020), 96 (2), 704-713CODEN: CBDDAL; ISSN:1747-0277. (Wiley-Blackwell)
    Acinetobacter baumannii is an opportunistic Gram-neg. bacterial pathogen, assocd. mostly with hospital-acquired infections. The emergence of drug resistance strains made it necessary to explore new pathways for the development of more effective antibiotics. Enoyl CoA reductase (FabI), a key enzyme in the fatty acid biosynthesis (FAS) pathway, has emerged as a potential target for antibacterial drug development. Earlier reports show that the lead SaFabI inhibitor AFN-1252 can inhibit FabI from other organisms including Escherichia coli and Burkholderia pseudomallei, but with differential potency. In the present work, we show that AFN-1252 is a moderate inhibitor of AbFabI with an IC50 of 216 nM. AFN-1252 stabilized AbFabI with a 4.2°C increase in the melting temp. (Tm) and, interestingly, the stabilization effect was significantly increased in presence of the cofactor NADH (ΔTm = 17°C), suggesting the formation of a ternary complex AbFabI: AFN-1252: NADH. X-ray crystallog. studies of AbFabI co-crystd. with AFN-1252 and NADH confirmed the ternary complex formation. The crit. interactions of AFN-1252 with AbFabI and NADH identified from the co-crystal structure may facilitate the design and development of new drugs against A. baumannii infections by targeting the FAS pathway.
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    Sihra, N.; Goodman, A.; Zakri, R.; Sahai, A.; Malde, S. Nonantibiotic prevention and management of recurrent urinary tract infection. Nat. Rev. Urol 2018, 15 (12), 750– 776,  DOI: 10.1038/s41585-018-0106-x
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    Nonantibiotic prevention and management of recurrent urinary tract infection
    Sihra Neha; Zakri Rhana; Sahai Arun; Malde Sachin; Goodman Anna
    Nature reviews. Urology (2018), 15 (12), 750-776 ISSN:.
    Urinary tract infections (UTIs) are highly prevalent, lead to considerable patient morbidity, incur large financial costs to health-care systems and are one of the most common reasons for antibiotic use worldwide. The growing problem of antimicrobial resistance means that the search for nonantibiotic alternatives for the treatment and prevention of UTI is of critical importance. Potential nonantibiotic measures and treatments for UTIs include behavioural changes, dietary supplementation (such as Chinese herbal medicines and cranberry products), NSAIDs, probiotics, D-mannose, methenamine hippurate, estrogens, intravesical glycosaminoglycans, immunostimulants, vaccines and inoculation with less-pathogenic bacteria. Some of the results of trials of these approaches are promising; however, high-level evidence is required before firm recommendations for their use can be made. A combination of these agents might provide the optimal treatment to reduce recurrent UTI, and trials in specific population groups are required.
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    Flores-Mireles, A. L.; Walker, J. N.; Caparon, M.; Hultgren, S. J. Urinary tract infections: epidemiology, mechanisms of infection and treatment options. Nat. Rev. Microbiol 2015, 13 (5), 269– 284,  DOI: 10.1038/nrmicro3432
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    Urinary tract infections: epidemiology, mechanisms of infection and treatment options
    Flores-Mireles, Ana L.; Walker, Jennifer N.; Caparon, Michael; Hultgren, Scott J.
    Nature Reviews Microbiology (2015), 13 (5), 269-284CODEN: NRMACK; ISSN:1740-1526. (Nature Publishing Group)
    Urinary tract infections (UTIs) are a severe public health problem and are caused by a range of pathogens, but most commonly by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterococcus faecalis and Staphylococcus saprophyticus. High recurrence rates and increasing antimicrobial resistance among uropathogens threaten to greatly increase the economic burden of these infections. In this Review, we discuss how basic science studies are elucidating the mol. details of the crosstalk that occurs at the host-pathogen interface, as well as the consequences of these interactions for the pathophysiol. of UTIs. We also describe current efforts to translate this knowledge into new clin. treatments for UTIs.
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    Goebel, M. C.; Trautner, B. W.; Grigoryan, L. The Five Ds of Outpatient Antibiotic Stewardship for Urinary Tract Infections. Clin Microbiol Rev. 2021, 34 (4), e0000320,  DOI: 10.1128/CMR.00003-20
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    Nielubowicz, G. R.; Mobley, H. L. Host-pathogen interactions in urinary tract infection. Nat. Rev. Urol 2010, 7 (8), 430– 441,  DOI: 10.1038/nrurol.2010.101
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    Host-pathogen interactions in urinary tract infection
    Nielubowicz, Greta R.; Mobley, Harry L. T.
    Nature Reviews Urology (2010), 7 (8), 430-441CODEN: NRNADQ; ISSN:1759-4812. (Nature Publishing Group)
    A review. Urinary tract infections are experienced by a large section of the population and cause significant morbidity. Here, Nielubowicz and Mobley explain the pathogenic mechanisms utilized by Escherichia coli and Proteus mirabilis during complicated and uncomplicated infection, resp. They outline the strategies currently underway to exploit these processes for the identification of new treatment options. The urinary tract is a common site of bacterial infections; nearly half of all women experience at least one urinary tract infection (UTI) during their lifetime. These infections are classified based on the condition of the host. Uncomplicated infections affect otherwise healthy individuals and are most commonly caused by uropathogenic Escherichia coli, whereas complicated infections affect patients with underlying difficulties, such as a urinary tract abnormality or catheterization, and are commonly caused by species such as Proteus mirabilis. Virulence and fitness factors produced by both pathogens include fimbriae, toxins, flagella, iron acquisition systems, and proteins that function in immune evasion. Addnl. factors that contribute to infection include the formation of intracellular bacterial communities by E. coli and the prodn. of urease by P. mirabilis, which can result in urinary stone formation. Innate immune responses are induced or mediated by pattern recognition receptors, antimicrobial peptides, and neutrophils. The adaptive immune response to UTI is less well understood. Host factors TLR4 and CXCR1 are implicated in disease outcome and susceptibility, resp. Low levels of TLR4 are assocd. with asymptomatic bacteriuria while low levels of CXCR1 are assocd. with increased incidence of acute pyelonephritis. Current research is focused on the identification of addnl. virulence factors and therapeutic or prophylactic targets that might be used in the generation of vaccines against both uropathogens.
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    Flamm, R. K.; Rhomberg, P. R.; Kaplan, N.; Jones, R. N.; Farrell, D. J. Activity of Debio1452, a FabI inhibitor with potent activity against Staphylococcus aureus and coagulase-negative Staphylococcus spp., including multidrug-resistant strains. Antimicrob. Agents Chemother. 2015, 59 (5), 2583– 2587,  DOI: 10.1128/AAC.05119-14
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    Activity of Debio1452, a FabI inhibitor with potent activity against Staphylococcus aureus and coagulase-negative Staphylococcus spp., including multidrug-resistant strains
    Flamm, Robert K.; Rhomberg, Paul R.; Kaplan, Nachum; Jones, Ronald N.; Farrell, David J.
    Antimicrobial Agents and Chemotherapy (2015), 59 (5), 2583-2587CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
    Staphylococcus aureus and coagulase-neg. staphylococci (CoNS) are responsible for a wide variety of human infections. The investigational antibacterial Debio1450 (previously AFN-1720), a prodrug of Debio1452 (previously AFN-1252), specifically targets staphylococci without significant activity against other Gram-pos. or Gram-neg. species. Debio1452 inhibits FabI, an enzyme crit. to fatty acid biosynthesis in staphylococci. The activity of Debio1452 against CoNS, methicillin-susceptible S. aureus (MSSA), and methicillin-resistant S. aureus (MRSA), including significant clones, was detd. A globally diverse collection of 574 patient isolates from 35 countries was tested that included CoNS (6 species, 103 strains), MSSA (154 strains), MRSA (163 strains), and molecularly characterized strains (including spa-typed MRSA clones; 154 strains). The isolates were tested for susceptibility by CLSI broth microdilution methods against Debio1452 and 10 comparators. The susceptibility rates for the comparators were detd. using CLSI and EUCAST breakpoint criteria. All S. aureus and CoNS strains were inhibited by Debio1452 concns. of ≤0.12 and ≤0.5 μg/mL, resp. The MIC50s for MSSA, MRSA, and molecularly characterized MRSA strains were 0.004 μg/mL, and the MIC90s ranged from 0.008 to 0.03 μg/mL. The MICs were higher for the CoNS isolates (MIC50/90, 0.015/0.12 μg/mL). Among S. aureus strains, resistance was common for erythromycin (61.6%), levofloxacin (49.0%), clindamycin (27.6%), tetracycline (15.7%), and trimethoprim-sulfamethoxazole (7.0%). Debio1452 demonstrated potent activity against MSSA, MRSA, and CoNS. Debio1452 showed significantly greater activity overall (MIC50, 0.004 μg/mL) than the other agents tested against these staphylococcal species, which included dominant MRSA clones and strains resistant to currently used antimicrobial agents.
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    Hafkin, B.; Kaplan, N.; Murphy, B. Efficacy and Safety of AFN-1252, the First Staphylococcus-Specific Antibacterial Agent, in the Treatment of Acute Bacterial Skin and Skin Structure Infections, Including Those in Patients with Significant Comorbidities. Antimicrob. Agents Chemother. 2016, 60 (3), 1695– 701,  DOI: 10.1128/AAC.01741-15
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    Efficacy and safety of AFN-1252, the first Staphylococcus-specific antibacterial agent, in the treatment of acute bacterial skin and skin structure infections, including those in patients with significant comorbidities
    Hafkin, B.; Kaplan, N.; Murphy, B.
    Antimicrobial Agents and Chemotherapy (2016), 60 (3), 1695-1701CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
    This open-label noncontrolled, phase II multicenter trial was designed to evaluate the safety, tolerability, and efficacy of 200 mg of AFN-1252, a selective inhibitor of Staphylococcus aureus enoyl-acyl carrier protein reductase (FabI), given by mouth twice daily in the treatment of acute bacterial skin and skin structure infections (ABSSSI) due to staphylococci. Important aspects of the current study included a comparison of early response efficacy endpoints with end-of-treatment and follow-up endpoints. Many patients in the intent-to-treat population (n = 103) had significant comorbidities. The overall early response rate at day 3 was 97.3% (wound, 100%; abscess, 96.6%; cellulitis, 94.4%) in the microbiol. evaluable (ME) population. Within the ME population, 82.9% of patients had a ≥ 20% decrease in the area of erythema, and 77.9% of patients had a ≥ 20% decrease in the area of induration, on day 3. S. aureus was detected in 97.7% of patients (n = 37 patients with methicillin-resistant S. aureus [MRSA], and n = 39 with methicillin-sensitive S. aureus [MSSA]). No isolates had increased AFN-1252 MICs posttreatment. Microbiol. eradication rates for S. aureus were 93.2% at short-term follow-up (STFU) and 91.9% at long-term follow-up (LTFU) in the ME population. Eradication rates for MRSA and MSSA were 91.9% and 92.3%, resp., at STFU and 91.9% and 89.7%, resp., at LTFU. The most frequently reported drug-related adverse events, which were mostly mild or moderate, were headache (26.2%) and nausea (21.4%). These studies demonstrate that AFN-1252 is generally well tolerated and effective in the treatment of ABSSSI due to S. aureus, including MRSA. This study has been registered at ClinicalTrials.gov under registration no.NCT01519492.
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    Radka, C. D.; Rock, C. O. Mining Fatty Acid Biosynthesis for New Antimicrobials. Annu. Rev. Microbiol. 2022, 76,  DOI: 10.1146/annurev-micro-041320-110408
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    Payne, D. J.; Warren, P. V.; Holmes, D. J.; Ji, Y.; Lonsdale, J. T. Bacterial fatty-acid biosynthesis: a genomics-driven target for antibacterial drug discovery. Drug Discov Today 2001, 6 (10), 537– 544,  DOI: 10.1016/S1359-6446(01)01774-3
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    Bacterial fatty-acid biosynthesis: a genomics-driven target for antibacterial drug discovery
    Payne, D. J.; Warren, P. V.; Holmes, D. J.; Ji, Y.; Lonsdale, J. T.
    Drug Discovery Today (2001), 6 (10), 537-544CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Science Ltd.)
    A review with 46 refs. demonstrating how the interplay of genomics, bioinformatics and genomic technologies has enabled an in-depth anal. of the component enzymes of the bacterial fatty-acid biosynthesis pathway as a source of novel antibacterial targets. This evaluation has revealed that many of the enzymes are potentially selective, broad-spectrum antibacterial targets. We also illustrate the suitability of some of these targets for HTS. Furthermore, we discuss how the availability of a robust selectivity assay, mode-of-action assays and numerous crystal structures provide an excellent set of tools with which to initiate integrated programs of research to identify novel antibiotics targeted at these enzymes.
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    Yao, J.; Rock, C. O. Bacterial fatty acid metabolism in modern antibiotic discovery. Biochim Biophys Acta Mol. Cell Biol. Lipids 2017, 1862 (11), 1300– 1309,  DOI: 10.1016/j.bbalip.2016.09.014
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    Bacterial fatty acid metabolism in modern antibiotic discovery
    Yao, Jiangwei; Rock, Charles O.
    Biochimica et Biophysica Acta, Molecular and Cell Biology of Lipids (2017), 1862 (11), 1300-1309CODEN: BBMLFG; ISSN:1388-1981. (Elsevier B.V.)
    Bacterial fatty acid synthesis is essential for many pathogens and different from the mammalian counterpart. These features make bacterial fatty acid synthesis a desirable target for antibiotic discovery. The structural divergence of the conserved enzymes and the presence of different isoenzymes catalyzing the same reactions in the pathway make bacterial fatty acid synthesis a narrow spectrum target rather than the traditional broad spectrum target. Furthermore, bacterial fatty acid synthesis inhibitors are single-targeting, rather than multi-targeting like traditional monotherapeutic, broad-spectrum antibiotics. The single-targeting nature of bacterial fatty acid synthesis inhibitors makes overcoming fast-developing, target-based resistance a necessary consideration for antibiotic development. Target-based resistance can be overcome through multi-targeting inhibitors, a cocktail of single-targeting inhibitors, or by making the single targeting inhibitor sufficiently high affinity through a pathogen selective approach such that target-based mutants are still susceptible to therapeutic concns. of drug. Many of the pathogens requiring new antibiotic treatment options encode for essential bacterial fatty acid synthesis enzymes. This review will evaluate the most promising targets in bacterial fatty acid metab. for antibiotic therapeutics development and review the potential and challenges in advancing each of these targets to the clinic and circumventing target-based resistance. This article is part of a Special Issue entitled: Bacterial Lipids edited by Russell E. Bishop.
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    Staley, C.; Vaughn, B. P.; Graiziger, C. T.; Sadowsky, M. J.; Khoruts, A. Gut-sparing treatment of urinary tract infection in patients at high risk of Clostridium difficile infection. J. Antimicrob. Chemother. 2017, 72 (2), 522– 528,  DOI: 10.1093/jac/dkw499
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    Gut-sparing treatment of urinary tract infection in patients at high risk of Clostridium difficile infection
    Staley, Christopher; Vaughn, Byron P.; Graiziger, Carolyn T.; Sadowsky, Michael J.; Khoruts, Alexander
    Journal of Antimicrobial Chemotherapy (2017), 72 (2), 522-528CODEN: JACHDX; ISSN:1460-2091. (Oxford University Press)
    Recipients of fecal microbiota transplantation (FMT) in treatment of recurrent Clostridium difficile infection (RCDI) remain at markedly increased risk of re-infection with C. difficile with new antibiotic provocations. Urinary tract infections (UTIs) are common indications for antibiotics in these patients, often resulting in C. difficile re-infection. We present a case series of 19 patients treated with parenteral aminoglycosides for UTI following FMT for RCDI. A 3 day outpatient regimen of once-daily i.m. administration of gentamicin was used to treat 18 consecutive FMT recipients with uncomplicated UTI. One other patient was treated for a complicated UTI with i.v. amikacin. Profiling of 16S rRNA genes was used to track changes in fecal microbial community structure during this regimen in three patients. The protocol was highly effective in treating UTI symptoms. None of the patients suffered a re-infection with C. difficile. The fecal microbial communities remained undisturbed by treatment with i.m. administration of gentamicin. Despite falling out of favor in recent years, aminoglycoside antibiotics given parenterally have the advantage of minimal penetration into the gut lumen. A brief (3 day) course of parenteral gentamicin was safe and effective in curing UTI in patients at high risk of C. difficile infection without perturbing their gut microbiota.
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    Worby, C. J.; Schreiber, H. L. t.; Straub, T. J.; van Dijk, L. R.; Bronson, R. A.; Olson, B. S.; Pinkner, J. S.; Obernuefemann, C. L. P.; Munoz, V. L.; Paharik, A. E.; Azimzadeh, P. N.; Walker, B. J.; Desjardins, C. A.; Chou, W. C.; Bergeron, K.; Chapman, S. B.; Klim, A.; Manson, A. L.; Hannan, T. J.; Hooton, T. M.; Kau, A. L.; Lai, H. H.; Dodson, K. W.; Hultgren, S. J.; Earl, A. M. Longitudinal multi-omics analyses link gut microbiome dysbiosis with recurrent urinary tract infections in women. Nat. Microbiol 2022, 7 (5), 630– 639,  DOI: 10.1038/s41564-022-01107-x
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    Longitudinal multi-omics analyses link gut microbiome dysbiosis with recurrent urinary tract infections in women
    Worby, Colin J.; Schreiber IV, Henry L.; Straub, Timothy J.; van Dijk, Lucas R.; Bronson, Ryan A.; Olson, Benjamin S.; Pinkner, Jerome S.; Obernuefemann, Chloe L. P.; Munoz, Vanessa L.; Paharik, Alexandra E.; Azimzadeh, Philippe N.; Walker, Bruce J.; Desjardins, Christopher A.; Chou, Wen-Chi; Bergeron, Karla; Chapman, Sinead B.; Klim, Aleksandra; Manson, Abigail L.; Hannan, Thomas J.; Hooton, Thomas M.; Kau, Andrew L.; Lai, H. Henry; Dodson, Karen W.; Hultgren, Scott J.; Earl, Ashlee M.
    Nature Microbiology (2022), 7 (5), 630-639CODEN: NMAICH; ISSN:2058-5276. (Nature Portfolio)
    Abstr.: Recurrent urinary tract infections (rUTIs) are a major health burden worldwide, with history of infection being a significant risk factor. While the gut is a known reservoir for uropathogenic bacteria, the role of the microbiota in rUTI remains unclear. We conducted a year-long study of women with (n = 15) and without (n = 16) history of rUTI, from whom we collected urine, blood and monthly faecal samples for metagenomic and transcriptomic interrogation. During the study 24 UTIs were reported, with addnl. samples collected during and after infection. The gut microbiome of individuals with a history of rUTI was significantly depleted in microbial richness and butyrate-producing bacteria compared with controls, reminiscent of other inflammatory conditions. However, Escherichia coli gut and bladder populations were comparable between cohorts in both relative abundance and phylogroup. Transcriptional anal. of peripheral blood mononuclear cells revealed expression profiles indicative of differential systemic immunity between cohorts. Altogether, these results suggest that rUTI susceptibility is in part mediated through the gut-bladder axis, comprising gut dysbiosis and differential immune response to bacterial bladder colonization, manifesting in symptoms.
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    Schembri, M. A.; Nhu, N. T. K.; Phan, M. D. Gut-bladder axis in recurrent UTI. Nat. Microbiol 2022, 7 (5), 601– 602,  DOI: 10.1038/s41564-022-01113-z
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    Gut-bladder axis in recurrent UTI
    Schembri, Mark A.; Nhu, Nguyen Thi Khanh; Phan, Minh-Duy
    Nature Microbiology (2022), 7 (5), 601-602CODEN: NMAICH; ISSN:2058-5276. (Nature Portfolio)
    Dysbiosis of the gut microbiome is assocd. with increased susceptibility to recurrent urinary tract infection, defining a gut-bladder axis.
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    Njoroge, M.; Kaur, G.; Espinoza-Moraga, M.; Wasuna, A.; Dziwornu, G. A.; Seldon, R.; Taylor, D.; Okombo, J.; Warner, D. F.; Chibale, K. Semisynthetic Antimycobacterial C-3 Silicate and C-3/C-21 Ester Derivatives of Fusidic Acid: Pharmacological Evaluation and Stability Studies in Liver Microsomes, Rat Plasma, and Mycobacterium tuberculosis culture. ACS Infect Dis 2019, 5 (9), 1634– 1644,  DOI: 10.1021/acsinfecdis.9b00208
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    Semisynthetic Antimycobacterial C-3 Silicate and C-3/C-21 Ester Derivatives of Fusidic Acid: Pharmacological Evaluation and Stability Studies in Liver Microsomes, Rat Plasma, and Mycobacterium tuberculosis culture
    Njoroge, Mathew; Kaur, Gurminder; Espinoza-Moraga, Marlene; Wasuna, Antonina; Dziwornu, Godwin Akpeko; Seldon, Ronnett; Taylor, Dale; Okombo, John; Warner, Digby F.; Chibale, Kelly
    ACS Infectious Diseases (2019), 5 (9), 1634-1644CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)
    Fusidic acid (FA), a natural product fusidane triterpene-based antibiotic with unique structural features, is active in vitro against Mycobacterium tuberculosis, the causative agent of tuberculosis (TB). While possessing good pharmacokinetics in man, FA is rapidly metabolized in rodents, thus complicating proof-of-concept studies in this model. Toward the repositioning of FA as an anti-TB agent, we herein describe the synthesis, activity, and metab. of FA and semisynthesized ester derivs. in rat liver microsomes, rat plasma, and mycobacterial cell culture. FA and deriv. mols. with a free C-3 OH underwent species-specific metab. to the corresponding 3-OH epimer, 3-epifusidic acid (3-epiFA). FA was also metabolized in rat plasma to form FA lactone. These addnl. routes of metab. may contribute to the more rapid clearance of FA obsd. in rodents. C-3 alkyl and aryl esters functioned as classic prodrugs of FA, being hydrolyzed to FA in microsomes, plasma, and Mycobacterium tuberculosis culture. In contrast, C-3 silicate esters and C-21 esters were inert to hydrolysis and so did not act as prodrugs. The antimycobacterial activity of the C-3 silicate esters was comparable to that of FA, and these compds. were stable in microsomes and plasma, identifying them as potential candidates for evaluation in a rodent model of tuberculosis.
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    Smith, P. W.; Zuccotto, F.; Bates, R. H.; Martinez-Martinez, M. S.; Read, K. D.; Peet, C.; Epemolu, O. Pharmacokinetics of beta-Lactam Antibiotics: Clues from the Past To Help Discover Long-Acting Oral Drugs in the Future. ACS Infect Dis 2018, 4 (10), 1439– 1447,  DOI: 10.1021/acsinfecdis.8b00160
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    Pharmacokinetics of β-Lactam Antibiotics: Clues from the Past To Help Discover Long-Acting Oral Drugs in the Future
    Smith, Paul W.; Zuccotto, Fabio; Bates, Robert H.; Martinez-Martinez, Maria Santos; Read, Kevin D.; Peet, Caroline; Epemolu, Ola
    ACS Infectious Diseases (2018), 4 (10), 1439-1447CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)
    A review. β-Lactams represent perhaps the most important class of antibiotics yet discovered. However, despite many years of active research, none of the currently approved drugs in this class combine oral activity with long duration of action. Recent developments suggest that new β-lactam antibiotics with such a profile would have utility in the treatment of tuberculosis. Consequently, the historical β-lactam pharmacokinetic data have been compiled and analyzed to identify possible directions and drug discovery strategies aimed toward new β-lactam antibiotics with this profile.
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  • Abstract

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    Figure 1

    Figure 1. FabI inhibitors. (A) Debio-1452 is highly potent against S. aureus; Debio-1452-NH3 retains this potency and gains modest activity against many Gram-negative pathogens. (B) The structure–activity relationship (SAR) of Debio-1452 showing regions amenable to substitution (highlighted in green) and those critical for antibacterial activity (highlighted in red).

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    Figure 2

    Figure 2. Debio-1452 analogue synthesis and antibacterial activity. The general synthetic route utilized to synthesize amine-containing compounds, and their antimicrobial activities against Gram-positive and Gram-negative bacteria. (†) indicates dose-independent trailing growth observed; see Supporting Information, Extended Data Figure S1. MIC values were determined using the microdilution broth method, as outlined by CLSI. All experiments were performed in biological triplicate. E. coli ΔtolC = JW5503.

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    Figure 3

    Figure 3. Optimized synthesis of fabimycin. The synthetic route used to access gram-scale quantities of fabimycin, utilizing dynamic kinetic resolution (DKR) to install the critical stereogenic center.

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    Figure 4

    Figure 4. Antimicrobial activity of fabimycin against clinical isolates. (A) The susceptibility of clinical isolates (Gram-negative species and S. aureus) to fabimycin, Debio-1452-NH3, and Debio-1452. MICs performed in biological triplicate. (B) Further exploration of the breadth of fabimycin’s antibacterial activity against diverse clinical isolate panels of K. pneumoniae and A. baumannii, as compared to levofloxacin. MICs performed in biological duplicate.

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    Figure 5

    Figure 5. Fabimycin mode of action studies. (A) Spontaneous resistance frequencies of S. aureus, E. coli, and A. baumannii versus fabimycin. Data represent three replicates for each pathogen with error bars representing the SEM. (B) Point mutations in FabI observed in fabimycin-resistant colonies, and the corresponding MIC values of fabimycin versus the mutants. All MICs were performed in biological triplicate.

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    Figure 6

    Figure 6. Co-crystal structures of fabimycin and its enantiomer with FabI. (A) Co-crystal structure of fabimycin with E. coli FabI with NADH cofactor (PDB 7UMW). (B) Co-crystal structure of (R)-7 in E. coli FabI with NADH cofactor (7UM8). (C) Water network surrounding fabimycin in the E. coli FabI active site. (D) Water network surrounding (R)-7 in the E. coli FabI active site.

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    Figure 7

    Figure 7. Computational and biophysical evaluation of fabimycin and its enantiomer. (A) Molecular dynamic simulations of fabimycin and its enantiomer using the co-crystal structures in E. coli FabI, demonstrating the enhanced flexibility (decreased stability) of (R)-7. (B) The determined enthalpy changes upon binding to FabI as assessed by isothermal titration calorimetry (ITC), as well as observed stabilization in a differential scanning fluorimetry assay of FabI (from E. coli and A. baumannii) upon compound binding relative to the holoenzyme. Tm values are means of technical triplicates with error shown as the standard deviation.

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    Figure 8

    Figure 8. Plasma stability and in vivo efficacy of fabimycin. (A) Assessment of fabimycin stability in plasma. Data shown as the mean and standard deviation from two experiments. (B) Acute pneumonia infections initiated in CD-1 mice with A. baumannii AR-0299 (1.6 × 108 CFUs per mouse intranasally). Mice were treated with vehicle (8 mice) or FabI inhibitor (8 mice per group) 4, 23, and 41 h postinfection (50 mg/kg intramuscular) and the bacterial burden evaluated at 48h postinfection. (C) Neutropenic mouse thigh infection initiated in CD-1 mice with A. baumannii AR-0299 (1.22 × 106 CFUs per mouse intramuscular in thigh) were treated with vehicle (8 mice) or FabI inhibitor (8 mice per group) 2, 6, and 11 h postinfection (50 mg/kg intramuscular), and the bacterial burden was evaluated 26h postinfection. (D) Neutropenic mouse thigh infection initiated in CD-1 mice with S. aureus USA300 LAC (2.3 × 106 CFU per mouse intramuscular in thigh) were treated with vehicle (eight mice) or FabI inhibitor (eight mice per group) 2 and 7 h postinfection (5 mg/kg retro-orbital IV), and the bacterial burden was evaluated 24 h postinfection. Debio-1452-tosylate used. FabI inhibitors formulated with 20% SBE-β-CD in H2O. In B, C, and D statistical significance was determined by one-way ANOVA with Tukey’s multiple comparisons. NS, not significant. ****P < 0.0001. Error bars represent standard deviation.

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    Figure 9

    Figure 9. In vivo efficacy of fabimycin in a murine UTI model. After inducing diuresis, infection initiated in C3H/HeJ mice (8 per arm, 1.38 * 109 CFU/mouse transurethral) with E. coli AR-0055 and treated with fabimycin (IV) at varying concentrations three times daily with bacterial enumeration at 168h postinfection. Fabimycin formulated in 17% Cremophor EL, 3% SBE-β-CD in H2O which was the formulation used in the vehicle arm (administered intravenously on the same schedule as fabimycin). Colistin was formulated in H2O with 0.9% NaCl and administered subcutaneously. Percentage in red indicates the percentage of animals with bacterial counts below the limit of detection (LOD, indicated by the dotted horizontal line). In A─D statistical significance was determined by one-way ANOVA with Tukey’s multiple comparisons. NS, not significant. *P = 0.0243, ***P < 0.001, ****P < 0.0001. Data represented as the mean with s.e.m.

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      Konychev, Alexander; Heep, Markus; Moritz, Rose K. C.; Kreuter, Alexander; Shulutko, Alexander; Fierlbeck, Gerhard; Bouylout, Kamel; Pathan, Rashidkhan; Trostmann, Uwe; Chaves, Ricardo L.
      Drugs & Aging (2013), 30 (10), 829-836CODEN: DRAGE6; ISSN:1170-229X. (Springer International Publishing AG)
      Background: Daptomycin has proven efficacy in patients with Gram-pos. complicated skin and soft tissue infections (cSSTIs), including those caused by Staphylococcus aureus, regardless of methicillin susceptibility. Objective: This study was undertaken to evaluate the efficacy and safety of daptomycin in elderly patients. Study Design: This was an open-label, multicentre, randomized phase IIIb study conducted in hospitalized patients Patients Patients aged ≥65 years with a diagnosis of Gram-pos. cSSTIs with or without bacteremia were included. In addn., infections were required to be of sufficient severity to require inpatient hospitalization and treatment with parenteral antibiotics for at least 96 h. The main exclusion criterion was the presence of a non-complicated SSTI that could heal by itself or be cured by surgical removal of the site of infection. Intervention: Patients were randomized 2:1 to i.v. daptomycin or pooled i.v. std. therapies semi-synthetic penicillin or vancomycin, referred to as the comparator. Duration of treatment was between 5 and 14 days for cSSTIs without bacteremia and between 10 and 28 days for cSSTIs with bacteremia. Main Outcome Measure: The primary objective was descriptive comparison of clin. success in clin. evaluable patients at test of cure, 7-14 days post treatment. Secondary objectives were microbiol. outcome, duration of treatment and safety. Results: In total, 120 patients were randomized (81 to daptomycin; 39 to the comparator) and 102 patients completed the study. Baseline characteristics were similar between the two groups. Common infections included cellulitis, ulcers and abscesses; six patients had bacteremia [five documented (daptomycin, n = 3; comparator, n = 2); and one suspected (daptomycin, n = 1)]. Test-of-cure clin. success rates were numerically higher for daptomycin than for the comparator [89.0 % (65/73) vs. 83.3 % (25/30); odds ratio 1.65 (95 % confidence interval 0.49-5.54)]. For patients with S. aureus infections, cure rates were 89.7 % (35/39) vs. 69.2 % (9/13), resp.; percentage points difference, 20.5 (95 % confidence interval -12.2 to 50.9). Rates of adverse events (AEs) and serious AEs were similar in both treatment arms; however, discontinuation rates for AEs/serious AEs were lower for daptomycin than for the comparator (3.8 % vs. 10.0 %). Three serious AEs were considered to be related to the study drug: one case each of pancytopenia (semi-synthetic penicillin), renal failure (vancomycin) and asymptomatic increase in creatine phosphokinase concns. (daptomycin). Conclusion: In elderly patients, for whom data were previously limited, the efficacy and safety of daptomycin have been confirmed, including for infections caused by S. aureus, regardless of methicillin susceptibility.
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    2. 2
      Moran, G. J.; Fang, E.; Corey, G. R.; Das, A. F.; De Anda, C.; Prokocimer, P. Tedizolid for 6 days versus linezolid for 10 days for acute bacterial skin and skin-structure infections (ESTABLISH-2): a randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis 2014, 14 (8), 696– 705,  DOI: 10.1016/S1473-3099(14)70737-6
      2
      Tedizolid for 6 days versus linezolid for 10 days for acute bacterial skin and skin-structure infections (ESTABLISH-2): a randomised, double-blind, phase 3, non-inferiority trial
      Moran, Gregory J.; Fang, Edward; Corey, G. Ralph; Das, Anita F.; De Anda, Carisa; Prokocimer, Philippe
      Lancet Infectious Diseases (2014), 14 (8), 696-705CODEN: LIDABP; ISSN:1473-3099. (Elsevier Ltd.)
      New antibiotics are needed to treat infections caused by drug-resistant bacteria. Tedizolid is a novel oxazolidinone antibacterial drug designed to provide enhanced activity against Gram-pos. pathogens. We aimed to assess the efficacy and safety of i.v. to oral tedizolid for treatment of patients with acute bacterial skin and skin-structure infections. ESTABLISH-2 was a randomised, double-blind, phase 3, non-inferiority trial done between Sept 28, 2011, and Jan 10, 2013, at 58 centers in nine countries. Patients (aged ≥12 years) with acute bacterial skin and skin-structure infections (cellulitis or erysipelas, major cutaneous abscess, or wound infection) that had a min. lesion area of 75 cm2 and were suspected or documented to be assocd. with a Gram-pos. pathogen, were randomly assigned (1:1), via an interactive voice-response system with block randomisation, to receive i.v. once-daily tedizolid (200 mg for 6 days) or twice-daily linezolid (600 mg for 10 days), with optional oral step-down. Randomisation was stratified by geog. region and type of acute bacterial skin and skin-structure infection. The primary endpoint was early clin. response (≥20% redn. in lesion area at 48-72 h compared with baseline), with a non-inferiority margin of -10%. Anal. was by intention to treat. This study is registered with ClinicalTrials.gov, no. NCT01421511.666 patients were randomly assigned to receive tedizolid (n=332) or linezolid (n=334). 283 (85%) patients in the tedizolid group and 276 (83%) in the linezolid group achieved early clin. response (difference 2·6%, 95% CI -3·0 to 8·2), meeting the prespecified non-inferiority margin. Gastrointestinal adverse events were less frequent with tedizolid than linezolid, taking place in 52 (16%) of 331 patients and 67 (20%) of 327 patients in the safety population. Treatment-emergent adverse events leading to discontinuation of study drug were reported by one (<1%) patient in the tedizolid group and four (1%) patients in the linezolid group. I.v. to oral once-daily tedizolid 200 mg for 6 days was non-inferior to twice-daily linezolid 600 mg for 10 days for treatment of patients with acute bacterial skin and skin-structure infections. Tedizolid could become a useful option for the treatment of acute bacterial skin and skin-structure infections in the hospital and outpatient settings.
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    3. 3
      File, T. M.; Goldberg, L.; Das, A.; Sweeney, C.; Saviski, J.; Gelone, S. P.; Seltzer, E.; Paukner, S.; Wicha, W. W.; Talbot, G. H.; Gasink, L. B. Efficacy and Safety of Intravenous-to-oral Lefamulin, a Pleuromutilin Antibiotic, for the Treatment of Community-acquired Bacterial Pneumonia: The Phase III Lefamulin Evaluation Against Pneumonia (LEAP 1) Trial. Clin Infect Dis 2019, 69 (11), 1856– 1867,  DOI: 10.1093/cid/ciz090
      3
      Efficacy and safety of intravenous-to-oral lefamulin, a pleuromutilin antibiotic, for the treatment of community-acquired bacterial pneumonia: the phase III lefamulin evaluation against pneumonia (LEAP 1) trial
      File, Thomas M., Jr.; Goldberg, Lisa; Das, Anita; Sweeney, Carolyn; Saviski, John; Gelone, Steven P.; Seltzer, Elyse; Paukner, Susanne; Wicha, Wolfgang W.; Talbot, George H.; Gasink, Leanne B.
      Clinical Infectious Diseases (2019), 69 (11), 1856-1867CODEN: CIDIEL; ISSN:1537-6591. (Oxford University Press)
      Lefamulin, a pleuromutilin antibiotic, is active against pathogens commonly causing community-acquired bacterial pneumonia (CABP). The Lefamulin Evaluation Against Pneumonia (LEAP 1) study was a global noninferiority trial to evaluate the efficacy and safety of lefamulin for the treatment of CABP. In this double-blind study, adults with CABP of Pneumonia Outcomes Research Team risk class ≥III were randomized 1:1 to receive lefamulin at 150 mg i.v. (IV) every 12 h or moxifloxacin at 400 mg IV every 24 h. After 6 doses, patients could be switched to an oral study drug if prespecified improvement criteria were met. If methicillin-resistant Staphylococcus aureus was suspected, either linezolid or placebo was added to moxifloxacin or lefamulin, resp. The US Food and Drug Administration primary endpoint was an early clin. response (ECR) 96 ± 24 h after the first dose of the study drug in the intent-to-treat (ITT) population (noninferiority margin, 12.5%). The European Medicines Agency co-primary endpoints were an investigator assessment of clin. response (IACR) 5-10 days after the last dose of the study drug in the modified ITT (mITT) and clin. evaluable (CE) populations (noninferiority margin, 10%). There were 551 patients randomized (n = 276 lefamulin; n = 275 moxifloxacin). Lefamulin was noninferior to moxifloxacin for ECR (87.3% vs 90.2%, resp.; difference -2.9%, 95% confidence interval [CI] g -8.5 to 2.8) and IACR (mITT, 81.7% vs 84.2%, resp.; difference -2.6%, 95% CI -8.9 to 3.9; CE, 86.9% vs 89.4%, resp.; difference -2.5%, 95% CI -8.4 to 3.4). Rates of study drug discontinuation due to treatment-emergent adverse events were 2.9% for lefamulin and 4.4% for moxifloxacin. Lefamulin was noninferior to moxifloxacin for the primary efficacy endpoints and was generally safe and well tolerated.
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    4. 4
      WHO Antibacterial products in clinical development for priority pathogens. https://www.who.int/observatories/global-observatory-on-health-research-and-development/monitoring/antibacterial-products-in-clinical-development-for-priority-pathogens (accessed June 13, 2022).
      There is no corresponding record for this reference.
    5. 5
      Rice, L. B. Federal funding for the study of antimicrobial resistance in nosocomial pathogens: no ESKAPE. J. Infect Dis 2008, 197 (8), 1079– 81,  DOI: 10.1086/533452
      5
      Federal funding for the study of antimicrobial resistance in nosocomial pathogens: no ESKAPE
      Rice Louis B
      The Journal of infectious diseases (2008), 197 (8), 1079-81 ISSN:0022-1899.
      There is no expanded citation for this reference.
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    6. 6
      Boucher, H. W.; Talbot, G. H.; Bradley, J. S.; Edwards, J. E.; Gilbert, D.; Rice, L. B.; Scheld, M.; Spellberg, B.; Bartlett, J. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis 2009, 48 (1), 1– 12,  DOI: 10.1086/595011
      6
      Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America
      Boucher Helen W; Talbot George H; Bradley John S; Edwards John E; Gilbert David; Rice Louis B; Scheld Michael; Spellberg Brad; Bartlett John
      Clinical infectious diseases : an official publication of the Infectious Diseases Society of America (2009), 48 (1), 1-12 ISSN:.
      The Infectious Diseases Society of America (IDSA) continues to view with concern the lean pipeline for novel therapeutics to treat drug-resistant infections, especially those caused by gram-negative pathogens. Infections now occur that are resistant to all current antibacterial options. Although the IDSA is encouraged by the prospect of success for some agents currently in preclinical development, there is an urgent, immediate need for new agents with activity against these panresistant organisms. There is no evidence that this need will be met in the foreseeable future. Furthermore, we remain concerned that the infrastructure for discovering and developing new antibacterials continues to stagnate, thereby risking the future pipeline of antibacterial drugs. The IDSA proposed solutions in its 2004 policy report, "Bad Bugs, No Drugs: As Antibiotic R&D Stagnates, a Public Health Crisis Brews," and recently issued a "Call to Action" to provide an update on the scope of the problem and the proposed solutions. A primary objective of these periodic reports is to encourage a community and legislative response to establish greater financial parity between the antimicrobial development and the development of other drugs. Although recent actions of the Food and Drug Administration and the 110th US Congress present a glimmer of hope, significant uncertainly remains. Now, more than ever, it is essential to create a robust and sustainable antibacterial research and development infrastructure--one that can respond to current antibacterial resistance now and anticipate evolving resistance. This challenge requires that industry, academia, the National Institutes of Health, the Food and Drug Administration, the Centers for Disease Control and Prevention, the US Department of Defense, and the new Biomedical Advanced Research and Development Authority at the Department of Health and Human Services work productively together. This report provides an update on potentially effective antibacterial drugs in the late-stage development pipeline, in the hope of encouraging such collaborative action.
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    7. 7
      Cassini, A.; Hogberg, L. D.; Plachouras, D.; Quattrocchi, A.; Hoxha, A.; Simonsen, G. S.; Colomb-Cotinat, M.; Kretzschmar, M. E.; Devleesschauwer, B.; Cecchini, M.; Ouakrim, D. A.; Oliveira, T. C.; Struelens, M. J.; Suetens, C.; Monnet, D. L.; the Burden of AMR Collective Group Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: a population-level modelling analysis. Lancet Infect. Dis. 2019, 19 (1), 56– 66,  DOI: 10.1016/S1473-3099(18)30605-4
      7
      Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: a population-level modelling analysis
      Cassini Alessandro; Hogberg Liselotte Diaz; Plachouras Diamantis; Quattrocchi Annalisa; Hoxha Ana; Struelens Marc J; Suetens Carl; Monnet Dominique L; Simonsen Gunnar Skov; Colomb-Cotinat Melanie; Kretzschmar Mirjam E; Devleesschauwer Brecht; Cecchini Michele; Ouakrim Driss Ait; Oliveira Tiago Cravo
      The Lancet. Infectious diseases (2019), 19 (1), 56-66 ISSN:.
      BACKGROUND: Infections due to antibiotic-resistant bacteria are threatening modern health care. However, estimating their incidence, complications, and attributable mortality is challenging. We aimed to estimate the burden of infections caused by antibiotic-resistant bacteria of public health concern in countries of the EU and European Economic Area (EEA) in 2015, measured in number of cases, attributable deaths, and disability-adjusted life-years (DALYs). METHODS: We estimated the incidence of infections with 16 antibiotic resistance-bacterium combinations from European Antimicrobial Resistance Surveillance Network (EARS-Net) 2015 data that was country-corrected for population coverage. We multiplied the number of bloodstream infections (BSIs) by a conversion factor derived from the European Centre for Disease Prevention and Control point prevalence survey of health-care-associated infections in European acute care hospitals in 2011-12 to estimate the number of non-BSIs. We developed disease outcome models for five types of infection on the basis of systematic reviews of the literature. FINDINGS: From EARS-Net data collected between Jan 1, 2015, and Dec 31, 2015, we estimated 671 689 (95% uncertainty interval [UI] 583 148-763 966) infections with antibiotic-resistant bacteria, of which 63·5% (426 277 of 671 689) were associated with health care. These infections accounted for an estimated 33 110 (28 480-38 430) attributable deaths and 874 541 (768 837-989 068) DALYs. The burden for the EU and EEA was highest in infants (aged <1 year) and people aged 65 years or older, had increased since 2007, and was highest in Italy and Greece. INTERPRETATION: Our results present the health burden of five types of infection with antibiotic-resistant bacteria expressed, for the first time, in DALYs. The estimated burden of infections with antibiotic-resistant bacteria in the EU and EEA is substantial compared with that of other infectious diseases, and has increased since 2007. Our burden estimates provide useful information for public health decision-makers prioritising interventions for infectious diseases. FUNDING: European Centre for Disease Prevention and Control.
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    8. 8
      Antimicrobial Resistance, C. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet 2022, 399 (10325), 629– 655,  DOI: 10.1016/S0140-6736(21)02724-0
      There is no corresponding record for this reference.
    9. 9
      Richter, M. F.; Drown, B. S.; Riley, A. P.; Garcia, A.; Shirai, T.; Svec, R. L.; Hergenrother, P. J. Predictive compound accumulation rules yield a broad-spectrum antibiotic. Nature 2017, 545 (7654), 299– 304,  DOI: 10.1038/nature22308
      9
      Predictive compound accumulation rules yield a broad-spectrum antibiotic
      Richter, Michelle F.; Drown, Bryon S.; Riley, Andrew P.; Garcia, Alfredo; Shirai, Tomohiro; Svec, Riley L.; Hergenrother, Paul J.
      Nature (London, United Kingdom) (2017), 545 (7654), 299-304CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      Most small mols. are unable to rapidly traverse the outer membrane of Gram-neg. bacteria and accumulate inside these cells, making the discovery of much-needed drugs against these pathogens challenging. Current understanding of the physicochem. properties that dictate small-mol. accumulation in Gram-neg. bacteria is largely based on retrospective analyses of antibacterial agents, which suggest that polarity and mol. wt. are key factors. Here the authors assess the ability of over 180 diverse compds. to accumulate in Escherichia coli. Computational anal. of the results reveals major differences from the retrospective studies, namely that the small mols. that are most likely to accumulate contain an amine, are amphiphilic and rigid, and have low globularity. These guidelines were then applied to convert deoxynybomycin, a natural product that is active only against Gram-pos. organisms, into an antibiotic with activity against a diverse panel of multi-drug-resistant Gram-neg. pathogens. The authors anticipate that these findings will aid in the discovery and development of antibiotics against Gram-neg. bacteria.
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    10. 10
      Zhao, S.; Adamiak, J. W.; Bonifay, V.; Mehla, J.; Zgurskaya, H. I.; Tan, D. S. Defining new chemical space for drug penetration into Gram-negative bacteria. Nat. Chem. Biol. 2020, 16 (12), 1293– 1302,  DOI: 10.1038/s41589-020-00674-6
      10
      Defining new chemical space for drug penetration into Gram-negative bacteria
      Zhao, Shibin; Adamiak, Justyna W.; Bonifay, Vincent; Mehla, Jitender; Zgurskaya, Helen I.; Tan, Derek S.
      Nature Chemical Biology (2020), 16 (12), 1293-1302CODEN: NCBABT; ISSN:1552-4450. (Nature Research)
      Abstr.: We live in the era of antibiotic resistance, and this problem will progressively worsen if no new solns. emerge. In particular, Gram-neg. pathogens present both biol. and chem. challenges that hinder the discovery of new antibacterial drugs. First, these bacteria are protected from a variety of structurally diverse drugs by a low-permeability barrier composed of two membranes with distinct permeability properties, in addn. to active drug efflux, making this cell envelope impermeable to most compds. Second, chem. libraries currently used in drug discovery contain few compds. that can penetrate Gram-neg. bacteria. As a result of these challenges, intensive screening campaigns have led to few successes, highlighting the need for new approaches to identify regions of chem. space that are specifically relevant to antibacterial drug discovery. Herein we provide an overview of emerging insights into this problem and outline a general approach to addressing it using prospective anal. of chem. libraries for the ability of compds. to accumulate in Gram-neg. bacteria. The overall goal is to develop robust cheminformatic tools to predict Gram-neg. permeation and efflux, which can then be used to guide medicinal chem. campaigns and the design of antibacterial discovery libraries.
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    11. 11
      Munoz, K. A.; Hergenrother, P. J. Facilitating Compound Entry as a Means to Discover Antibiotics for Gram-Negative Bacteria. Acc. Chem. Res. 2021, 54 (6), 1322– 1333,  DOI: 10.1021/acs.accounts.0c00895
      11
      Facilitating Compound Entry as a Means to Discover Antibiotics for Gram-Negative Bacteria
      Munoz, Kristen A.; Hergenrother, Paul J.
      Accounts of Chemical Research (2021), 54 (6), 1322-1333CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
      A review. It has been over half a century since the last class of antibiotics active against the most problematic Gram-neg. bacteria was approved by the Food and Drug Administration (FDA). The major challenge with developing antibiotics to treat these infections is not drug-target engagement but rather the inability of most small mols. to traverse the Gram-neg. membranes, be retained, and accumulate within the cell. Despite an abundance of lead compds., limited understanding of the physicochem. properties needed for compd. accumulation (or avoidance of efflux) in Gram-neg. bacteria has precluded a generalizable approach for developing Gram-neg. antibiotics. Indeed, in many instances, despite years of intensive derivatization efforts and the synthesis of hundreds of compds. aimed at building in Gram-neg. activity, little or no progress has been made in expanding the spectrum of activity for many Gram-pos.-only antibiotics. We describe the discovery and successful applications of a promising strategy for enhancing the accumulation of Gram-pos.-only antibiotics as a means of imbuing compds. with broad-spectrum activity. Utilizing a prospective approach examg. the accumulation in Escherichia coli for >180 diverse compds., we found that small mols. have an increased likelihood to accumulate in E. coli when they contain an ionizable nitrogen, have low 3-dimensionality, and are rigid. Implementing these guidelines, codified as the eNTRy rules and assisted by web application www.entry-way.org, we have facilitated compd. entry and systematically built Gram-neg. activity into Gram-pos.-only antibiotics. Though each antibiotic will have case-specific considerations, we describe a set of important criteria to consider when selecting candidate Gram-pos.-only antibiotics for conversion to Gram-neg.-active versions via the eNTRy rules. As detailed herein, using this blueprint the spectrum of activity was expanded for 3 antibiotic classes that engage 3 different biol. targets: DNA gyrase inhibitor 6DNM, FabI inhibitor Debio-1452, and FMN riboswitch inhibitor Ribocil C. In each scenario, the eNTRy rules guided the synthesis of key analogs predisposed to accumulate in Gram-neg. bacteria leading to compds. that display antibiotic activity (min. inhibitory concns. (MIC) ≤8μg/mL) against E. coli and other Gram-neg. ESKAPE pathogens. While the eNTRy rules will continue to be refined and enhanced as more accumulation data is gathered, on the basis of these collective results and on other examples not covered herein it is clear that the eNTRy rules are actionable for the development of novel broad-spectrum antibiotics from Gram-pos.-only compds. By enabling the prediction of compd. accumulation, the eNTRy rules should facilitate the process of discovering and developing novel antibiotics active against Gram-neg. bacteria.
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    12. 12
      Payne, D. J.; Gwynn, M. N.; Holmes, D. J.; Pompliano, D. L. Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat. Rev. Drug Discov 2007, 6 (1), 29– 40,  DOI: 10.1038/nrd2201
      12
      Drugs for bad bugs: confronting the challenges of antibacterial discovery
      Payne, David J.; Gwynn, Michael N.; Holmes, David J.; Pompliano, David L.
      Nature Reviews Drug Discovery (2007), 6 (1), 29-40CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
      A review. The sequencing of the first complete bacterial genome in 1995 heralded a new era of hope for antibacterial drug discoverers, who now had the tools to search entire genomes for new antibacterial targets. Several companies, including GlaxoSmithKline, moved back into the antibacterials area and embraced a genomics-derived, target-based approach to screen for new classes of drugs with novel modes of action. Here, we share our experience of evaluating more than 300 genes and 70 high-throughput screening campaigns over a period of 7 years, and look at what we learned and how that has influenced GlaxoSmithKline's antibacterials strategy going forward.
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    13. 13
      Tommasi, R.; Brown, D. G.; Walkup, G. K.; Manchester, J. I.; Miller, A. A. ESKAPEing the labyrinth of antibacterial discovery. Nat. Rev. Drug Discov 2015, 14 (8), 529– 42,  DOI: 10.1038/nrd4572
      13
      ESKAPEing the labyrinth of antibacterial discovery
      Tommasi, Ruben; Brown, Dean G.; Walkup, Grant K.; Manchester, John I.; Miller, Alita A.
      Nature Reviews Drug Discovery (2015), 14 (8), 529-542CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
      A review. Antimicrobial drug resistance is a growing threat to global public health. Multidrug resistance among the 'ESKAPE' organisms - encompassing Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp. - is of particular concern because they are responsible for many serious infections in hospitals. Although some promising agents are in the pipeline, there is an urgent need for new antibiotic scaffolds. However, antibacterial researchers have struggled to identify new small mols. with meaningful cellular activity, esp. those effective against multidrug-resistant Gram-neg. pathogens. This difficulty ultimately stems from an incomplete understanding of efflux systems and compd. permeation through bacterial membranes. This Opinion article describes findings from target-based and phenotypic screening efforts carried out at AstraZeneca over the past decade, discusses some of the subsequent chem. challenges and concludes with a description of new approaches comprising a combination of computational modeling and advanced biol. tools which may pave the way towards the discovery of new antibacterial agents.
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    14. 14
      Yao, J.; Rock, C. O. Resistance Mechanisms and the Future of Bacterial Enoyl-Acyl Carrier Protein Reductase (FabI) Antibiotics. Cold Spring Harb Perspect Med. 2016, 6 (3), a027045,  DOI: 10.1101/cshperspect.a027045
      There is no corresponding record for this reference.
    15. 15
      Seefeld, M. A.; Miller, W. H.; Newlander, K. A.; Burgess, W. J.; Payne, D. J.; Rittenhouse, S. F.; Moore, T. D.; DeWolf, W. E., Jr.; Keller, P. M.; Qiu, X.; Janson, C. A.; Vaidya, K.; Fosberry, A. P.; Smyth, M. G.; Jaworski, D. D.; Slater-Radosti, C.; Huffman, W. F. Inhibitors of bacterial enoyl acyl carrier protein reductase (FabI): 2,9-disubstituted 1,2,3,4-tetrahydropyrido[3,4-b]indoles as potential antibacterial agents. Bioorg. Med. Chem. Lett. 2001, 11 (17), 2241– 4,  DOI: 10.1016/S0960-894X(01)00405-X
      15
      Inhibitors of bacterial enoyl acyl carrier protein reductase (FabI): 2,9-disubstituted 1,2,3,4-tetrahydropyrido[3,4-b]indoles as potential antibacterial agents
      Seefeld, M. A.; Miller, W. H.; Newlander, K. A.; Burgess, W. J.; Payne, D. J.; Rittenhouse, S. F.; Moore, T. D.; DeWolf, W. E.; Keller, P. M.; Qiu, X.; Janson, C. A.; Vaidya, K.; Fosberry, A. P.; Smyth, M. G.; Jaworski, D. D.; Slater-Radosti, C.; Huffman, W. F.
      Bioorganic & Medicinal Chemistry Letters (2001), 11 (17), 2241-2244CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)
      An SAR study of a screening lead has led to the identification of 2,9-disubstituted 1,2,3,4-tetrahydropyrido[3,4-b]indoles as inhibitors of Staphylococcus aureus enoyl acyl carrier protein reductase (FabI).
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXmt1yqtbY%253D&md5=6904b75740db275d6defbbc08009a6eb
    16. 16
      Payne, D. J.; Miller, W. H.; Berry, V.; Brosky, J.; Burgess, W. J.; Chen, E.; DeWolf Jr, W. E., Jr.; Fosberry, A. P.; Greenwood, R.; Head, M. S.; Heerding, D. A.; Janson, C. A.; Jaworski, D. D.; Keller, P. M.; Manley, P. J.; Moore, T. D.; Newlander, K. A.; Pearson, S.; Polizzi, B. J.; Qiu, X.; Rittenhouse, S. F.; Slater-Radosti, C.; Salyers, K. L.; Seefeld, M. A.; Smyth, M. G.; Takata, D. T.; Uzinskas, I. N.; Vaidya, K.; Wallis, N. G.; Winram, S. B.; Yuan, C. C.; Huffman, W. F. Discovery of a novel and potent class of FabI-directed antibacterial agents. Antimicrob. Agents Chemother. 2002, 46 (10), 3118– 24,  DOI: 10.1128/AAC.46.10.3118-3124.2002
      16
      Discovery of a novel and potent class of FabI-directed antibacterial agents
      Payne, David J.; Miller, William H.; Berry, Valerie; Brosky, John; Burgess, Walter J.; Chen, Emile; DeWolf, Walter E., Jr.; Fosberry, Andrew P.; Greenwood, Rebecca; Head, Martha S.; Heerding, Dirk A.; Janson, Cheryl A.; Jaworski, Deborah D.; Keller, Paul M.; Manley, Peter J.; Moore, Terrance D.; Newlander, Kenneth A.; Pearson, Stewart; Polizzi, Brian J.; Qiu, Xiayang; Rittenhouse, Stephen F.; Slater-Radosti, Courtney; Salyers, Kevin L.; Seefeld, Mark A.; Smyth, Martin G.; Takata, Dennis T.; Uzinskas, Irene N.; Vaidya, Kalindi; Wallis, Nicola G.; Winram, Scott B.; Yuan, Catherine C. K.; Huffman, William F.
      Antimicrobial Agents and Chemotherapy (2002), 46 (10), 3118-3124CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
      Bacterial enoyl-acyl carrier protein (ACP) reductase (FabI) catalyzes the final step in each elongation cycle of bacterial fatty acid biosynthesis and is an attractive target for the development of new antibacterial agents. High-throughput screening of the Staphylococcus aureus FabI enzyme identified a novel, weak inhibitor with no detectable antibacterial activity against S. aureus. Iterative medicinal chem. and x-ray crystal structure-based design led to the identification of compd. 4 [(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide], which is 350-fold more potent than the original lead compd. obtained by high-throughput screening in the FabI inhibition assay. Compd. 4 has exquisite antistaphylococci activity, achieving MICs at which 90% of isolates are inhibited more than 500 times lower than those of nine currently available antibiotics against a panel of multidrug-resistant strains of S. aureus and Staphylococcus epidermidis. Furthermore, compd. 4 exhibits excellent in vivo efficacy in an S. aureus infection model in rats. Biochem. and genetic approaches have confirmed that the mode of antibacterial action of compd. 4 and related compd. is via inhibition of FabI. Compd. 4 also exhibits weak FabK inhibitory activity, which may explain its antibacterial activity against Streptococcus pneumoniae and Enterococcus faecalis, which depend on FabK and both FabK and FabI, resp., for their enoyl-ACP reductase function. These results show that compd. 4 is representative of a new, totally synthetic series of antibacterial agents that has the potential to provide novel alternatives for the treatment of S. aureus infections that are resistant to our present armory of antibiotics.
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    17. 17
      Wittke, F.; Vincent, C.; Chen, J.; Heller, B.; Kabler, H.; Overcash, J. S.; Leylavergne, F.; Dieppois, G. Afabicin, a First-in-Class Antistaphylococcal Antibiotic, in the Treatment of Acute Bacterial Skin and Skin Structure Infections: Clinical Noninferiority to Vancomycin/Linezolid. Antimicrob. Agents Chemother. 2020, 64 (10), e00250-20,  DOI: 10.1128/AAC.00250-20
      There is no corresponding record for this reference.
    18. 18
      Karlowsky, J. A.; Kaplan, N.; Hafkin, B.; Hoban, D. J.; Zhanel, G. G. AFN-1252, a FabI inhibitor, demonstrates a Staphylococcus-specific spectrum of activity. Antimicrob. Agents Chemother. 2009, 53 (8), 3544– 8,  DOI: 10.1128/AAC.00400-09
      18
      AFN-1252, a FabI inhibitor, demonstrates a staphylococcus-specific spectrum of activity
      Karlowsky, James A.; Kaplan, Nachum; Hafkin, Barry; Hoban, Daryl J.; Zhanel, George G.
      Antimicrobial Agents and Chemotherapy (2009), 53 (8), 3544-3548CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
      AFN-1252, a potent inhibitor of enoyl-acyl carrier protein reductase (FabI), inhibited all clin. isolates of Staphylococcus aureus (n = 502) and Staphylococcus epidermidis (n = 51) tested, including methicillin (methicillin)-resistant isolates, at concns. of ≤0.12 μg/mL. In contrast, AFN-1252 was inactive (MIC90, >4 μg/mL) against clin. isolates of Streptococcus pneumoniae, beta-hemolytic streptococci, Enterococcus spp., Enterobacteriaceae, nonfermentative gram-neg. bacilli, and Moraxella catarrhalis. These data support the continued development of AFN-1252 for the treatment of patients with resistant staphylococcal infections.
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    19. 19
      Parker, E. N.; Drown, B. S.; Geddes, E. J.; Lee, H. Y.; Ismail, N.; Lau, G. W.; Hergenrother, P. J. Implementation of permeation rules leads to a FabI inhibitor with activity against Gram-negative pathogens. Nat. Microbiol 2020, 5 (1), 67– 75,  DOI: 10.1038/s41564-019-0604-5
      19
      Implementation of permeation rules leads to a FabI inhibitor with activity against Gram-negative pathogens
      Parker, Erica N.; Drown, Bryon S.; Geddes, Emily J.; Lee, Hyang Yeon; Ismail, Nahed; Lau, Gee W.; Hergenrother, Paul J.
      Nature Microbiology (2020), 5 (1), 67-75CODEN: NMAICH; ISSN:2058-5276. (Nature Research)
      Gram-neg. bacterial infections are a significant public health concern, and the lack of new drug classes for these pathogens is linked to the inability of most drug leads to accumulate inside Gram-neg. bacteria1-7. Here, we report the development of a web application-eNTRyway-that predicts compd. accumulation (in Escherichia coli) from its structure. In conjunction with structure-activity relationships and X-ray data, eNTRyway was utilized to re-design Debio-1452-a Gram-pos.-only antibiotic8-into versions that accumulate in E. coli and possess antibacterial activity against high-priority Gram-neg. pathogens. The lead compd. Debio-1452-NH3 operates as an antibiotic via the same mechanism as Debio-1452, namely potent inhibition of the enoyl-acyl carrier protein reductase FabI, as validated by in vitro enzyme assays and the generation of bacterial isolates with spontaneous target mutations. Debio-1452-NH3 is well tolerated in vivo, reduces bacterial burden in mice and rescues mice from lethal infections with clin. isolates of Acinetobacter baumannii, Klebsiella pneumoniae and E. coli. This work provides tools for the facile discovery and development of high-accumulating compds. in E. coli, and a general blueprint for the conversion of Gram-pos.-only compds. into broad-spectrum antibiotics.
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    20. 20
      Richter, M. F.; Hergenrother, P. J. The challenge of converting Gram-positive-only compounds into broad-spectrum antibiotics. Ann. N.Y. Acad. Sci. 2019, 1435 (1), 18– 38,  DOI: 10.1111/nyas.13598
      20
      The challenge of converting Gram-positive-only compounds into broad-spectrum antibiotics
      Richter, Michelle F.; Hergenrother, Paul J.
      Annals of the New York Academy of Sciences (2019), 1435 (1, Antimicrobial Therapeutics Reviews), 18-38CODEN: ANYAA9; ISSN:0077-8923. (John Wiley & Sons, Inc.)
      A review. Multidrug resistant Gram-neg. bacterial infections are on the rise, and there is a lack of new classes of drugs to treat these pathogens. This drug shortage is largely due to the challenge of finding antibiotics that can permeate and persist inside Gram-neg. species. Efforts to understand the mol. properties that enable certain compds. to accumulate in Gram-neg. bacteria based on retrospective studies of known antibiotics have not been generally actionable in the development of new antibiotics. A recent assessment of the ability of >180 diverse small mols. to accumulate in Escherichia coli led to predictive guidelines for compd. accumulation in E. coli. These "eNTRy rules" state that compds. are most likely to accumulate if they contain a nonsterically encumbered ionizable Nitrogen (primary amines are the best), have low Three-dimensionality (globularity ≤ 0.25), and are relatively Rigid (rotatable bonds ≤ 5). In this review, we look back through 50+ years of antibacterial research and 1000s of derivs. and assess this historical data set through the lens of these predictive guidelines. The results are consistent with the eNTRy rules, suggesting that the eNTRy rules may provide an actionable and general roadmap for the conversion of Gram-pos.-only compds. into broad-spectrum antibiotics.
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    21. 21
      Kaplan, N.; Albert, M.; Awrey, D.; Bardouniotis, E.; Berman, J.; Clarke, T.; Dorsey, M.; Hafkin, B.; Ramnauth, J.; Romanov, V.; Schmid, M. B.; Thalakada, R.; Yethon, J.; Pauls, H. W. Mode of action, in vitro activity, and in vivo efficacy of AFN-1252, a selective antistaphylococcal FabI inhibitor. Antimicrob. Agents Chemother. 2012, 56 (11), 5865– 5874,  DOI: 10.1128/AAC.01411-12
      21
      Mode of action, in vitro activity, and in vivo efficacy of AFN-1252, a selective antistaphylococcal FabI inhibitor
      Kaplan, Nachum; Albert, Monique; Awrey, Donald; Bardouniotis, Elias; Berman, Judd; Clarke, Teresa; Dorsey, Mandy; Hafkin, Barry; Ramnauth, Jaillal; Romanov, Vladimir; Schmid, Molly B.; Thalakada, Rosanne; Yethon, Jeremy; Pauls, Henry W.
      Antimicrobial Agents and Chemotherapy (2012), 56 (11), 5865-5874CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
      The mechanism of action of AFN-1252, a selective inhibitor of Staphylococcus aureus enoyl-acyl carrier protein reductase (FabI), which is involved in fatty acid biosynthesis, was confirmed by using biochem., macromol. synthesis, genetics, and co-crystn. of an AFN-1252-FabI complex. AFN-1252 demonstrated a low propensity for spontaneous resistance development and a time-dependent redn. of the viability of both methicillin-susceptible and methicillin-resistant S. aureus, achieving a ≥2-log10 redn. in S. aureus counts over 24 h, and was extremely potent against clin. isolates of S. aureus (MIC90, 0.015 μg/mL) and coagulase-neg. staphylococci (MIC90, 0.12 μg/mL), regardless of their drug resistance, hospital- or community-assocd. origin, or other clin. subgroup. AFN-1252 was orally available in mouse pharmacokinetic studies, and a single oral dose of 1 mg/kg AFN-1252 was efficacious in a mouse model of septicemia, providing 100% protection from an otherwise lethal peritoneal infection of S. aureus Smith. A median ED of 0.15 mg/kg indicated that AFN-1252 was 12 to 24 times more potent than linezolid in the model. These studies, demonstrating a selective mode of action, potent in vitro activity, and in vivo efficacy, support the continued investigation of AFN-1252 as a targeted therapeutic for staphylococcal infections.
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    22. 22
      Seefeld, M. A.; Miller, W. H.; Newlander, K. A.; Burgess, W. J.; DeWolf, W. E., Jr.; Elkins, P. A.; Head, M. S.; Jakas, D. R.; Janson, C. A.; Keller, P. M.; Manley, P. J.; Moore, T. D.; Payne, D. J.; Pearson, S.; Polizzi, B. J.; Qiu, X.; Rittenhouse, S. F.; Uzinskas, I. N.; Wallis, N. G.; Huffman, W. F. Indole naphthyridinones as inhibitors of bacterial enoyl-ACP reductases FabI and FabK. J. Med. Chem. 2003, 46 (9), 1627– 35,  DOI: 10.1021/jm0204035
      22
      Indole Naphthyridinones as Inhibitors of Bacterial Enoyl-ACP Reductases FabI and FabK
      Seefeld, Mark A.; Miller, William H.; Newlander, Kenneth A.; Burgess, Walter J.; DeWolf, Walter E., Jr.; Elkins, Patricia A.; Head, Martha S.; Jakas, Dalia R.; Janson, Cheryl A.; Keller, Paul M.; Manley, Peter J.; Moore, Terrance D.; Payne, David J.; Pearson, Stewart; Polizzi, Brian J.; Qiu, Xiayang; Rittenhouse, Stephen F.; Uzinskas, Irene N.; Wallis, Nicola G.; Huffman, William F.
      Journal of Medicinal Chemistry (2003), 46 (9), 1627-1635CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Bacterial enoyl-ACP reductase (FabI) is responsible for catalyzing the final step of bacterial fatty acid biosynthesis and is an attractive target for the development of novel antibacterial agents. Previously we reported the development of FabI inhibitor 4 with narrow spectrum antimicrobial activity and in vivo efficacy against Staphylococcus aureus via i.p. administration. Through iterative medicinal chem. aided by x-ray crystal structure anal., a new series of inhibitors has been developed with greatly increased potency against FabI-contg. organisms. Several of these new inhibitors have potent antibacterial activity against multidrug resistant strains of S. aureus, and compd. 30 demonstrates exceptional oral (po) in vivo efficacy in a S. aureus infection model in rats. While optimizing FabI inhibitory activity, compds. 29 and 30 were identified as having low micromolar FabK inhibitory activity, thereby increasing the antimicrobial spectrum of these compds. to include the FabK-contg. pathogens Streptococcus pneumoniae and Enterococcus faecalis. The results described herein support the hypothesis that bacterial enoyl-ACP reductases are valid targets for antibacterial agents.
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    23. 23
      Ramnauth, J.; Surman, M. D.; Sampson, P. B.; Forrest, B.; Wilson, J.; Freeman, E.; Manning, D. D.; Martin, F.; Toro, A.; Domagala, M.; Awrey, D. E.; Bardouniotis, E.; Kaplan, N.; Berman, J.; Pauls, H. W. 2,3,4,5-Tetrahydro-1H-pyrido[2,3-b and e][1,4]diazepines as inhibitors of the bacterial enoyl ACP reductase, FabI. Bioorg. Med. Chem. Lett. 2009, 19 (18), 5359– 5362,  DOI: 10.1016/j.bmcl.2009.07.094
      23
      2,3,4,5-Tetrahydro-1H-pyrido[2,3-b and e][1,4]diazepines as inhibitors of the bacterial enoyl ACP reductase, FabI
      Ramnauth, Jailall; Surman, Mathew D.; Sampson, Peter B.; Forrest, Bryan; Wilson, Jeff; Freeman, Emily; Manning, David D.; Martin, Fernando; Toro, Andras; Domagala, Megan; Awrey, Donald E.; Bardouniotis, Elias; Kaplan, Nachum; Berman, Judd; Pauls, Henry W.
      Bioorganic & Medicinal Chemistry Letters (2009), 19 (18), 5359-5362CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      In the search for new antibacterial agents, the enzyme FabI has been identified as an attractive target. Employing a structure guided approach, the previously reported ene-amide series of FabI inhibitors were expanded to include 2,3,4,5-tetrahydro-1H-pyrido[2,3-b and e][1,4]diazepines, e.g. I (R = 1-methyl-2-indolyl, 3-methyl-2-benzofuranyl, etc.; X = H2, O) and II. These novel series incorporate addnl. H-bonding functions and can be more water sol. than their naphthyridinone progenitors; diazepine II (R = 1-methyl-2-indolyl; X = O) is shown to be efficacious in a mouse infection model.
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    24. 24
      Takhi, M.; Sreenivas, K.; Reddy, C. K.; Munikumar, M.; Praveena, K.; Sudheer, P.; Rao, B. N.; Ramakanth, G.; Sivaranjani, J.; Mulik, S.; Reddy, Y. R.; Narasimha Rao, K.; Pallavi, R.; Lakshminarasimhan, A.; Panigrahi, S. K.; Antony, T.; Abdullah, I.; Lee, Y. K.; Ramachandra, M.; Yusof, R.; Rahman, N. A.; Subramanya, H. Discovery of azetidine based ene-amides as potent bacterial enoyl ACP reductase (FabI) inhibitors. Eur. J. Med. Chem. 2014, 84, 382– 394,  DOI: 10.1016/j.ejmech.2014.07.036
      24
      Discovery of azetidine based ene-amides as potent bacterial enoyl ACP reductase (FabI) inhibitors
      Takhi, Mohamed; Sreenivas, Kandepu; Reddy, Chandrashekar K.; Munikumar, Mahadari; Praveena, Kolakota; Sudheer, Pabolu; Rao, Bandaru N. V. M.; Ramakanth, Gollamudi; Sivaranjani, Jampala; Mulik, Shardaprasad; Reddy, Yeruva R.; Narasimha Rao, Krishnamurthy; Pallavi, Rentala; Lakshminarasimhan, Anirudha; Panigrahi, Sunil K.; Antony, Thomas; Abdullah, Iskandar; Lee, Yean K.; Ramachandra, Murali; Yusof, Rohana; Rahman, Noorsaadah A.; Subramanya, Hosahalli
      European Journal of Medicinal Chemistry (2014), 84 (), 382-394CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
      A novel and potent series of ene-amides featuring azetidines has been developed as FabI inhibitors active against drug resistant Gram-pos. pathogens particularly staphylococcal organisms. Most of the compds. from the series possessed excellent biochem. inhibition of Staphylococcus aureus FabI enzyme and whole cell activity against clin. relevant MRSA, MSSA and MRSE organisms which are responsible for significant morbidity and mortality in community as well as hospital settings. The binding mode of one of the leads, I, in Escherichia coli FabI enzyme was detd. unambiguously using x-ray crystallog. The lead compds. displayed good metabolic stability in mice liver microsomes and pharmacokinetic profile in mice. The in vivo efficacy of lead AEA16 has been demonstrated in a lethal murine systemic infection model.
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    25. 25
      Hergenrother, P. J.; Geddes, E. J.; Drown, B. S.; Motika, S. E.; Parker, S. E. Antibiotics Effective for Gram-Negative Pathogens. WO2019/177975A1, 2019.
      There is no corresponding record for this reference.
    26. 26
      Gerusz, V. B.; Bravo, J.; Pauls, H.; Berman, J.; Finn, T. Novel Compounds and their Use. WO2021/123372A1, 2021.
      There is no corresponding record for this reference.
    27. 27
      Hergenrother, P. J.; Parker, E. N.; Hung, D.; Serrano-Wu, M.; Lee, K. K. FabI inhibitors for Gram-negative pathogens. US Provisional Patent Application No. 63/156,145. 2021.
      There is no corresponding record for this reference.
    28. 28
      Geddes, E. J.; Li, Z.; Hergenrother, P. J. An LC-MS/MS assay and complementary web-based tool to quantify and predict compound accumulation in E. coli. Nat. Protoc 2021, 16 (10), 4833– 4854,  DOI: 10.1038/s41596-021-00598-y
      27
      An LC-MS/MS assay and complementary web-based tool to quantify and predict compound accumulation in E. coli
      Geddes, Emily J.; Li, Zhong; Hergenrother, Paul J.
      Nature Protocols (2021), 16 (10), 4833-4854CODEN: NPARDW; ISSN:1750-2799. (Nature Portfolio)
      A review. Novel classes of broad-spectrum antibiotics have been extremely difficult to discover, largely due to the impermeability of the Gram-neg. membranes coupled with a poor understanding of the physicochem. properties a compd. should possess to promote its accumulation inside the cell. To address this challenge, numerous methodologies for assessing intracellular compd. accumulation in Gram-neg. bacteria have been established, including classic radiometric and fluorescence-based methods. The recent development of accumulation assays that utilize liq. chromatog.-tandem mass spectrometry (LC-MS/MS) have circumvented the requirement for labeled compds., enabling assessment of a substantially broader range of small mols. Our unbiased study of accumulation trends in Escherichia coli using an LC-MS/MS-based assay led to the development of the eNTRy rules, which stipulate that a compd. is most likely to accumulate in E. coli if it has an ionizable Nitrogen, has low Three-dimensionality and is relatively Rigid. To aid in the implementation of the eNTRy rules, we developed a complementary web tool, eNTRyway, which calcs. relevant properties and predicts compd. accumulation. Here we provide a comprehensive protocol for anal. and prediction of intracellular accumulation of small mols. in E. coli using an LC-MS/MS-based assay (which takes ∼2 d) and eNTRyway, a workflow that is readily adoptable by any microbiol., biochem. or chem. biol. lab.
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    29. 29
      Zhu, L.; Lin, J.; Ma, J.; Cronan, J. E.; Wang, H. Triclosan resistance of Pseudomonas aeruginosa PAO1 is due to FabV, a triclosan-resistant enoyl-acyl carrier protein reductase. Antimicrob. Agents Chemother. 2010, 54 (2), 689– 698,  DOI: 10.1128/AAC.01152-09
      28
      Triclosan resistance of Pseudomonas aeruginosa PAO1 is due to FabV, a triclosan-resistant enoyl-acyl carrier protein reductase
      Zhu, Lei; Lin, Jinshui; Ma, Jincheng; Cronan, John E.; Wang, Haihong
      Antimicrobial Agents and Chemotherapy (2010), 54 (2), 689-698CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
      Triclosan, a very widely used biocide, specifically inhibits fatty acid synthesis by inhibition of enoyl-acyl carrier protein (ACP) reductase. Escherichia coli FabI is the prototypical triclosan-sensitive enoyl-ACP reductase, and E. coli is extremely sensitive to the biocide. However, other bacteria are resistant to triclosan, because they encode triclosan-resistant enoyl-ACP reductase isoenzymes. In contrast, the triclosan resistance of Pseudomonas aeruginosa PAO1 has been attributed to active efflux of the compd. We report that P. aeruginosa contains two enoyl-ACP reductase isoenzymes, the previously characterized FabI homolog plus a homolog of FabV, a triclosan-resistant enoyl-ACP reductase recently demonstrated in Vibrio cholerae. By deletion of the genes encoding P. aeruginosa FabI and FabV, we demonstrated that FabV confers triclosan resistance on P. aeruginosa. Upon deletion of the fabV gene, the mutant strain became extremely sensitive to triclosan (>2,000-fold more sensitive than the wild-type strain), whereas the mutant strain lacking FabI remained completely resistant to the biocide.
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    30. 30
      Parsons, J. B.; Frank, M. W.; Subramanian, C.; Saenkham, P.; Rock, C. O. Metabolic basis for the differential susceptibility of Gram-positive pathogens to fatty acid synthesis inhibitors. Proc. Natl. Acad. Sci. U. S. A. 2011, 108 (37), 15378– 15383,  DOI: 10.1073/pnas.1109208108
      29
      Metabolic basis for the differential susceptibility of gram-positive pathogens to fatty acid synthesis inhibitors
      Parsons, Joshua B.; Frank, Matthew W.; Subramanian, Chitra; Saenkham, Panatda; Rock, Charles O.
      Proceedings of the National Academy of Sciences of the United States of America (2011), 108 (37), 15378-15383, S15378/1-S15378/10CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      The rationale for the pursuit of bacterial type 2 fatty acid synthesis (FASII) as a target for antibacterial drug discovery in Gram-pos. organisms is being debated vigorously based on their ability to incorporate extracellular fatty acids. The regulation of FASII by extracellular fatty acids was examd. in Staphylococcus aureus and Streptococcus pneumoniae, representing two important groups of pathogens. Both bacteria use the same enzymic tool kit for the conversion of extracellular fatty acids to acyl-acyl carrier protein, elongation, and incorporation into phospholipids. Exogenous fatty acids completely replace the endogenous fatty acids in S. pneumoniae but support only 50% of phospholipid synthesis in S. aureus. Fatty acids overcame FASII inhibition in S. pneumoniae but not in S. aureus. Extracellular fatty acids strongly suppress malonyl-CoA levels in S. pneumoniae but not in S. aureus, showing a feedback regulatory system in S. pneumoniae that is absent in S. aureus. Fatty acids overcame either a biochem. or a genetic block at acetyl-CoA carboxylase (ACC) in S. aureus, confirming that regulation at the ACC step is the key difference between these two species. Bacteria that possess a stringent biochem. feedback inhibition of ACC and malonyl-CoA formation triggered by environmental fatty acids are able to circumvent FASII inhibition. However, if exogenous fatty acids do not suppress malonyl-CoA formation, FASII inhibitors remain effective in the presence of fatty acid supplements.
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    31. 31
      Zhu, L.; Bi, H.; Ma, J.; Hu, Z.; Zhang, W.; Cronan, J. E.; Wang, H. The two functional enoyl-acyl carrier protein reductases of Enterococcus faecalis do not mediate triclosan resistance. mBio 2013, 4 (5), e00613– 13,  DOI: 10.1128/mBio.00613-13
      30
      The two functional enoyl-acyl carrier protein reductases of Enterococcus faecalis do not mediate triclosan resistance
      Zhu, Lei; Bi, Hongkai; Ma, Jincheng; Hu, Zhe; Zhang, Wenbin; Cronan, John E.; Wang, Haihong
      mBio (2013), 4 (5), e00613/1-e00613/11CODEN: MBIOCL; ISSN:2150-7511. (American Society for Microbiology)
      Enoyl-acyl carrier protein (enoyl-ACP) reductase catalyzes the last step of the elongation cycle in the synthesis of bacterial fatty acids. The Enterococcus faecalis genome contains two genes annotated as enoyl-ACP reductases, a FabI-type enoyl- ACP reductase and a FabK-type enoyl-ACP reductase. The authors report that expression of either of the two proteins restores growth of an Escherichia coli fabI temp.-sensitive mutant strain under nonpermissive conditions. In vitro assays demonstrated that both proteins support fatty acid synthesis and are active with substrates of all fatty acid chain lengths. Although expression of E. faecalis fabK confers to E. coli high levels of resistance to the antimicrobial triclosan, deletion of fabK from the E. faecalis genome showed that FabK does not play a detectable role in the inherent triclosan resistance of E. faecalis. Indeed, FabK seems to play only a minor role in modulating fatty acid compn. Strains carrying a deletion of fabK grow normally without fatty acid supplementation, whereas fabI deletion mutants make only traces of fatty acids and are unsatd. fatty acid auxotrophs.
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    32. 32
      Yao, J.; Carter, R. A.; Vuagniaux, G.; Barbier, M.; Rosch, J. W.; Rock, C. O. A Pathogen-Selective Antibiotic Minimizes Disturbance to the Microbiome. Antimicrob. Agents Chemother. 2016, 60 (7), 4264– 73,  DOI: 10.1128/AAC.00535-16
      31
      A pathogen-selective antibiotic minimizes disturbance to the microbiome
      Yao, Jiangwei; Carter, Robert A.; Vuagniaux, Gregoire; Barbier, Maryse; Rosch, Jason W.; Rock, Charles O.
      Antimicrobial Agents and Chemotherapy (2016), 60 (7), 4264-4273CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
      Broad-spectrum antibiotic therapy decimates the gut microbiome, resulting in a variety of neg. health consequences. Debio 1452 is a staphylococcus-selective enoyl-acyl carrier protein reductase (FabI) inhibitor under clin. development and was used to det. whether treatment with pathogen-selective antibiotics would minimize disturbance to the microbiome. The effect of oral Debio 1452 on the microbiota of mice was compared to the effects of four commonly used broad-spectrum oral antibiotics. During the 10 days of oral Debio 1452 treatment, there was minimal disturbance to the gut bacterial abundance and compn., with only the unclassified S24-7 taxon reduced at days 6 and 10. In comparison, broad-spectrum oral antibiotics caused ∼100- to 4000-fold decreases in gut bacterial abundance and severely altered the microbial compn. The gut bacterial abundance and compn. of Debio 1452-treated mice were indistinguishable from those of untreated mice 2 days after the antibiotic treatment was stopped. In contrast, the bacterial abundance in broad-spectrum-antibiotic-treated mice took up to 7 days to recover, and the gut compn. of the broad-spectrum-antibiotic-treated mice remained different from that of the control group 20 days after the cessation of antibiotic treatment. These results illustrate that a pathogen-selective approach to antibiotic development will minimize disturbance to the gut microbiome.
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    33. 33
      Imai, Y.; Meyer, K. J.; Iinishi, A.; Favre-Godal, Q.; Green, R.; Manuse, S.; Caboni, M.; Mori, M.; Niles, S.; Ghiglieri, M.; Honrao, C.; Ma, X.; Guo, J. J.; Makriyannis, A.; Linares-Otoya, L.; Bohringer, N.; Wuisan, Z. G.; Kaur, H.; Wu, R.; Mateus, A.; Typas, A.; Savitski, M. M.; Espinoza, J. L.; O’Rourke, A.; Nelson, K. E.; Hiller, S.; Noinaj, N.; Schaberle, T. F.; D’Onofrio, A.; Lewis, K. A new antibiotic selectively kills Gram-negative pathogens. Nature 2019, 576 (7787), 459– 464,  DOI: 10.1038/s41586-019-1791-1
      32
      A new antibiotic selectively kills Gram-negative pathogens
      Imai, Yu; Meyer, Kirsten J.; Iinishi, Akira; Favre-Godal, Quentin; Green, Robert; Manuse, Sylvie; Caboni, Mariaelena; Mori, Miho; Niles, Samantha; Ghiglieri, Meghan; Honrao, Chandrashekhar; Ma, Xiaoyu; Guo, Jason J.; Makriyannis, Alexandros; Linares-Otoya, Luis; Bohringer, Nils; Wuisan, Zerlina G.; Kaur, Hundeep; Wu, Runrun; Mateus, Andre; Typas, Athanasios; Savitski, Mikhail M.; Espinoza, Josh L.; O'Rourke, Aubrie; Nelson, Karen E.; Hiller, Sebastian; Noinaj, Nicholas; Schaberle, Till F.; D'Onofrio, Anthony; Lewis, Kim
      Nature (London, United Kingdom) (2019), 576 (7787), 459-464CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
      The current need for novel antibiotics is esp. acute for drug-resistant Gram-neg. pathogens1,2. These microorganisms have a highly restrictive permeability barrier, which limits the penetration of most compds.3,4. As a result, the last class of antibiotics that acted against Gram-neg. bacteria was developed in the 1960s2. We reason that useful compds. can be found in bacteria that share similar requirements for antibiotics with humans, and focus on Photorhabdus symbionts of entomopathogenic nematode microbiomes. Here we report a new antibiotic that we name darobactin, which was obtained using a screen of Photorhabdus isolates. Darobactin is coded by a silent operon with little prodn. under lab. conditions, and is ribosomally synthesized. Darobactin has an unusual structure with two fused rings that form post-translationally. The compd. is active against important Gram-neg. pathogens both in vitro and in animal models of infection. Mutants that are resistant to darobactin map to BamA, an essential chaperone and translocator that folds outer membrane proteins. Our study suggests that bacterial symbionts of animals contain antibiotics that are particularly suitable for development into therapeutics.
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    34. 34
      Leimer, N.; Wu, X.; Imai, Y.; Morrissette, M.; Pitt, N.; Favre-Godal, Q.; Iinishi, A.; Jain, S.; Caboni, M.; Leus, I. V.; Bonifay, V.; Niles, S.; Bargabos, R.; Ghiglieri, M.; Corsetti, R.; Krumpoch, M.; Fox, G.; Son, S.; Klepacki, D.; Polikanov, Y. S.; Freliech, C. A.; McCarthy, J. E.; Edmondson, D. G.; Norris, S. J.; D’Onofrio, A.; Hu, L. T.; Zgurskaya, H. I.; Lewis, K. A selective antibiotic for Lyme disease. Cell 2021, 184 (21), 5405– 5418,  DOI: 10.1016/j.cell.2021.09.011
      33
      A selective antibiotic for Lyme disease
      Leimer, Nadja; Wu, Xiaoqian; Imai, Yu; Morrissette, Madeleine; Pitt, Norman; Favre-Godal, Quentin; Iinishi, Akira; Jain, Samta; Caboni, Mariaelena; Leus, Inga V.; Bonifay, Vincent; Niles, Samantha; Bargabos, Rachel; Ghiglieri, Meghan; Corsetti, Rachel; Krumpoch, Megan; Fox, Gabriel; Son, Sangkeun; Klepacki, Dorota; Polikanov, Yury S.; Freliech, Cecily A.; McCarthy, Julie E.; Edmondson, Diane G.; Norris, Steven J.; D'Onofrio, Anthony; Hu, Linden T.; Zgurskaya, Helen I.; Lewis, Kim
      Cell (Cambridge, MA, United States) (2021), 184 (21), 5405-5418.e16CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
      Lyme disease is on the rise. Caused by a spirochete Borreliella burgdorferi, it affects an estd. 500,000 people in the United States alone. The antibiotics currently used to treat Lyme disease are broad spectrum, damage the microbiome, and select for resistance in non-target bacteria. We therefore sought to identify a compd. acting selectively against B. burgdorferi. A screen of soil micro-organisms revealed a compd. highly selective against spirochetes, including B. burgdorferi. Unexpectedly, this compd. was detd. to be hygromycin A, a known antimicrobial produced by Streptomyces hygroscopicus. Hygromycin A targets the ribosomes and is taken up by B. burgdorferi, explaining its selectivity. Hygromycin A cleared the B. burgdorferi infection in mice, including animals that ingested the compd. in a bait, and was less disruptive to the fecal microbiome than clin. relevant antibiotics. This selective antibiotic holds the promise of providing a better therapeutic for Lyme disease and eradicating it in the environment.
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    35. 35
      Poyet, M.; Groussin, M.; Gibbons, S. M.; Avila-Pacheco, J.; Jiang, X.; Kearney, S. M.; Perrotta, A. R.; Berdy, B.; Zhao, S.; Lieberman, T. D.; Swanson, P. K.; Smith, M.; Roesemann, S.; Alexander, J. E.; Rich, S. A.; Livny, J.; Vlamakis, H.; Clish, C.; Bullock, K.; Deik, A.; Scott, J.; Pierce, K. A.; Xavier, R. J.; Alm, E. J. A library of human gut bacterial isolates paired with longitudinal multiomics data enables mechanistic microbiome research. Nat. Med. 2019, 25 (9), 1442– 1452,  DOI: 10.1038/s41591-019-0559-3
      34
      A library of human gut bacterial isolates paired with longitudinal multiomics data enables mechanistic microbiome research
      Poyet, M.; Groussin, M.; Gibbons, S. M.; Avila-Pacheco, J.; Jiang, X.; Kearney, S. M.; Perrotta, A. R.; Berdy, B.; Zhao, S.; Lieberman, T. D.; Swanson, P. K.; Smith, M.; Roesemann, S.; Alexander, J. E.; Rich, S. A.; Livny, J.; Vlamakis, H.; Clish, C.; Bullock, K.; Deik, A.; Scott, J.; Pierce, K. A.; Xavier, R. J.; Alm, E. J.
      Nature Medicine (New York, NY, United States) (2019), 25 (9), 1442-1452CODEN: NAMEFI; ISSN:1078-8956. (Nature Research)
      Our understanding of how the gut microbiome interacts with its human host has been restrained by limited access to longitudinal datasets to examine stability and dynamics, and by having only a few isolates to test mechanistic hypotheses. Here, we present the Broad Institute-OpenBiome Microbiome Library (BIO-ML), a comprehensive collection of 7,758 gut bacterial isolates paired with 3,632 genome sequences and longitudinal multi-omics data. We show that microbial species maintain stable population sizes within and across humans and that commonly used 'omics' survey methods are more reliable when using avs. over multiple days of sampling. Variation of gut metabolites within people over time is assocd. with amino acid levels, and differences across people are assocd. with differences in bile acids. Finally, we show that genomic diversification can be used to infer eco-evolutionary dynamics and in vivo selection pressures for strains within individuals. The BIO-ML is a unique resource designed to enable hypothesis-driven microbiome research.
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    36. 36
      Marrakchi, H.; Dewolf, W. E., Jr.; Quinn, C.; West, J.; Polizzi, B. J.; So, C. Y.; Holmes, D. J.; Reed, S. L.; Heath, R. J.; Payne, D. J.; Rock, C. O.; Wallis, N. G. Characterization of Streptococcus pneumoniae enoyl-(acyl-carrier protein) reductase (FabK). Biochem. J. 2003, 370 (3), 1055– 1062,  DOI: 10.1042/bj20021699
      35
      Characterization of Streptococcus pneumoniae enoyl-(acyl-carrier protein) reductase (FabK)
      Marrakchi, Hedia; Dewolf, Walter E., Jr.; Quinn, Chad; West, Joshua; Polizzi, Brian J.; So, Chi Y.; Holmes, David J.; Reed, Shannon L.; Heath, Richard J.; Payne, David J.; Rock, Charles O.; Wallis, Nicola G.
      Biochemical Journal (2003), 370 (3), 1055-1062CODEN: BIJOAK; ISSN:0264-6021. (Portland Press Ltd.)
      The enoyl-(acyl-carrier protein) (ACP) reductase catalyzes the last step in each cycle of fatty acid elongation in the type II fatty acid synthase systems. An extensively characterized NADH-dependent reductase, FabI, is widely distributed in bacteria and plants, whereas the enoyl-ACP reductase, FabK, is a distinctly different member of this enzyme group discovered in Streptococcus pneumoniae . We were unable to delete the fabK gene from Strep. pneumoniae , suggesting that this is the only enoyl-ACP reductase in this organism. The FabK enzyme was purified and the biochem. properties of the reductase were examd. The visible absorption spectrum of the purified protein indicated the presence of a flavin cofactor that was identified as FMN by MS, and was present in a 1:1 molar ratio with protein. FabK specifically required NADH and the protein activity was stimulated by ammonium ions. FabK also exhibited NADH oxidase activity in the absence of substrate. Strep. pneumoniae belongs to the Bacillus/Lactobacillus/Streptococcus group that includes Staphylococcus aureus and Bacillus subtilis . These two organisms also contain FabK-related genes, suggesting that they may also express a FabK-like enoyl-ACP reductase. However, the genes did not complement a fabI (Ts) mutant and the purified flavoproteins were unable to reduce enoyl-ACP in vitro and did not exhibit NAD(P)H oxidase activity, indicating they were not enoyl-ACP reductases. The restricted occurrence of the FabK enoyl-ACP reductase may be related to the role of substrate-independent NADH oxidn. in oxygen-dependent anaerobic energy metab.
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    37. 37
      Armstrong, J. D.; Eng, K. K.; Keller, J. L.; Purick, R. M.; Hartner, F. W.; Choi, W.-B.; Askin, D.; Volante, R.P. An Efficient Asymmetric Synthesis of (R)-3-Amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one. Tetrahedron Lett. 1994, 35 (20), 3239– 3242,  DOI: 10.1016/S0040-4039(00)76874-2
      36
      An efficient asymmetric synthesis of (R)-3-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one
      Armstrong, Joseph D., III; Eng, Kan K.; Keller, Jennifer L.; Purick, Robert M.; Hartner, Frederick W., Jr.; Choi, Woo-Baeg; Askin, David; Volante, R. P.
      Tetrahedron Letters (1994), 35 (20), 3239-42CODEN: TELEAY; ISSN:0040-4039.
      Two approaches for the asym. prepn. of (-)- or (+)-α-aminobenzlactam I are described. One route is based on the asym. hydrogenation of enamide II and the other on the racemization/resoln. of (±)-I.
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    38. 38
      Galac, M. R.; Snesrud, E.; Lebreton, F.; Stam, J.; Julius, M.; Ong, A. C.; Maybank, R.; Jones, A. R.; Kwak, Y. I.; Hinkle, K.; Waterman, P. E.; Lesho, E. P.; Bennett, J. W.; Mc Gann, P. A Diverse Panel of Clinical Acinetobacter baumannii for Research and Development. Antimicrob. Agents Chemother. 2020, 64 (10), e00840-20,  DOI: 10.1128/AAC.00840-20
      There is no corresponding record for this reference.
    39. 39
      Rao, N. K.; Nataraj, V.; Ravi, M.; Panchariya, L.; Palai, K.; Talapati, S. R.; Lakshminarasimhan, A.; Ramachandra, M.; Antony, T. Ternary complex formation of AFN-1252 with Acinetobacter baumannii FabI and NADH: Crystallographic and biochemical studies. Chem. Biol. Drug Des 2020, 96 (2), 704– 713,  DOI: 10.1111/cbdd.13686
      38
      Ternary complex formation of AFN-1252 with Acinetobacter baumannii FabI and NADH: Crystallographic and biochemical studies
      Rao, Narasimha K.; Nataraj, Vijayashankar; Ravi, Mohan; Panchariya, Love; Palai, Kirttija; Talapati, Sumalatha R.; Lakshminarasimhan, Anirudha; Ramachandra, Murali; Antony, Thomas
      Chemical Biology & Drug Design (2020), 96 (2), 704-713CODEN: CBDDAL; ISSN:1747-0277. (Wiley-Blackwell)
      Acinetobacter baumannii is an opportunistic Gram-neg. bacterial pathogen, assocd. mostly with hospital-acquired infections. The emergence of drug resistance strains made it necessary to explore new pathways for the development of more effective antibiotics. Enoyl CoA reductase (FabI), a key enzyme in the fatty acid biosynthesis (FAS) pathway, has emerged as a potential target for antibacterial drug development. Earlier reports show that the lead SaFabI inhibitor AFN-1252 can inhibit FabI from other organisms including Escherichia coli and Burkholderia pseudomallei, but with differential potency. In the present work, we show that AFN-1252 is a moderate inhibitor of AbFabI with an IC50 of 216 nM. AFN-1252 stabilized AbFabI with a 4.2°C increase in the melting temp. (Tm) and, interestingly, the stabilization effect was significantly increased in presence of the cofactor NADH (ΔTm = 17°C), suggesting the formation of a ternary complex AbFabI: AFN-1252: NADH. X-ray crystallog. studies of AbFabI co-crystd. with AFN-1252 and NADH confirmed the ternary complex formation. The crit. interactions of AFN-1252 with AbFabI and NADH identified from the co-crystal structure may facilitate the design and development of new drugs against A. baumannii infections by targeting the FAS pathway.
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    40. 40
      Sihra, N.; Goodman, A.; Zakri, R.; Sahai, A.; Malde, S. Nonantibiotic prevention and management of recurrent urinary tract infection. Nat. Rev. Urol 2018, 15 (12), 750– 776,  DOI: 10.1038/s41585-018-0106-x
      39
      Nonantibiotic prevention and management of recurrent urinary tract infection
      Sihra Neha; Zakri Rhana; Sahai Arun; Malde Sachin; Goodman Anna
      Nature reviews. Urology (2018), 15 (12), 750-776 ISSN:.
      Urinary tract infections (UTIs) are highly prevalent, lead to considerable patient morbidity, incur large financial costs to health-care systems and are one of the most common reasons for antibiotic use worldwide. The growing problem of antimicrobial resistance means that the search for nonantibiotic alternatives for the treatment and prevention of UTI is of critical importance. Potential nonantibiotic measures and treatments for UTIs include behavioural changes, dietary supplementation (such as Chinese herbal medicines and cranberry products), NSAIDs, probiotics, D-mannose, methenamine hippurate, estrogens, intravesical glycosaminoglycans, immunostimulants, vaccines and inoculation with less-pathogenic bacteria. Some of the results of trials of these approaches are promising; however, high-level evidence is required before firm recommendations for their use can be made. A combination of these agents might provide the optimal treatment to reduce recurrent UTI, and trials in specific population groups are required.
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    41. 41
      Flores-Mireles, A. L.; Walker, J. N.; Caparon, M.; Hultgren, S. J. Urinary tract infections: epidemiology, mechanisms of infection and treatment options. Nat. Rev. Microbiol 2015, 13 (5), 269– 284,  DOI: 10.1038/nrmicro3432
      40
      Urinary tract infections: epidemiology, mechanisms of infection and treatment options
      Flores-Mireles, Ana L.; Walker, Jennifer N.; Caparon, Michael; Hultgren, Scott J.
      Nature Reviews Microbiology (2015), 13 (5), 269-284CODEN: NRMACK; ISSN:1740-1526. (Nature Publishing Group)
      Urinary tract infections (UTIs) are a severe public health problem and are caused by a range of pathogens, but most commonly by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterococcus faecalis and Staphylococcus saprophyticus. High recurrence rates and increasing antimicrobial resistance among uropathogens threaten to greatly increase the economic burden of these infections. In this Review, we discuss how basic science studies are elucidating the mol. details of the crosstalk that occurs at the host-pathogen interface, as well as the consequences of these interactions for the pathophysiol. of UTIs. We also describe current efforts to translate this knowledge into new clin. treatments for UTIs.
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    42. 42
      Goebel, M. C.; Trautner, B. W.; Grigoryan, L. The Five Ds of Outpatient Antibiotic Stewardship for Urinary Tract Infections. Clin Microbiol Rev. 2021, 34 (4), e0000320,  DOI: 10.1128/CMR.00003-20
      There is no corresponding record for this reference.
    43. 43
      Nielubowicz, G. R.; Mobley, H. L. Host-pathogen interactions in urinary tract infection. Nat. Rev. Urol 2010, 7 (8), 430– 441,  DOI: 10.1038/nrurol.2010.101
      42
      Host-pathogen interactions in urinary tract infection
      Nielubowicz, Greta R.; Mobley, Harry L. T.
      Nature Reviews Urology (2010), 7 (8), 430-441CODEN: NRNADQ; ISSN:1759-4812. (Nature Publishing Group)
      A review. Urinary tract infections are experienced by a large section of the population and cause significant morbidity. Here, Nielubowicz and Mobley explain the pathogenic mechanisms utilized by Escherichia coli and Proteus mirabilis during complicated and uncomplicated infection, resp. They outline the strategies currently underway to exploit these processes for the identification of new treatment options. The urinary tract is a common site of bacterial infections; nearly half of all women experience at least one urinary tract infection (UTI) during their lifetime. These infections are classified based on the condition of the host. Uncomplicated infections affect otherwise healthy individuals and are most commonly caused by uropathogenic Escherichia coli, whereas complicated infections affect patients with underlying difficulties, such as a urinary tract abnormality or catheterization, and are commonly caused by species such as Proteus mirabilis. Virulence and fitness factors produced by both pathogens include fimbriae, toxins, flagella, iron acquisition systems, and proteins that function in immune evasion. Addnl. factors that contribute to infection include the formation of intracellular bacterial communities by E. coli and the prodn. of urease by P. mirabilis, which can result in urinary stone formation. Innate immune responses are induced or mediated by pattern recognition receptors, antimicrobial peptides, and neutrophils. The adaptive immune response to UTI is less well understood. Host factors TLR4 and CXCR1 are implicated in disease outcome and susceptibility, resp. Low levels of TLR4 are assocd. with asymptomatic bacteriuria while low levels of CXCR1 are assocd. with increased incidence of acute pyelonephritis. Current research is focused on the identification of addnl. virulence factors and therapeutic or prophylactic targets that might be used in the generation of vaccines against both uropathogens.
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    44. 44
      Flamm, R. K.; Rhomberg, P. R.; Kaplan, N.; Jones, R. N.; Farrell, D. J. Activity of Debio1452, a FabI inhibitor with potent activity against Staphylococcus aureus and coagulase-negative Staphylococcus spp., including multidrug-resistant strains. Antimicrob. Agents Chemother. 2015, 59 (5), 2583– 2587,  DOI: 10.1128/AAC.05119-14
      43
      Activity of Debio1452, a FabI inhibitor with potent activity against Staphylococcus aureus and coagulase-negative Staphylococcus spp., including multidrug-resistant strains
      Flamm, Robert K.; Rhomberg, Paul R.; Kaplan, Nachum; Jones, Ronald N.; Farrell, David J.
      Antimicrobial Agents and Chemotherapy (2015), 59 (5), 2583-2587CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
      Staphylococcus aureus and coagulase-neg. staphylococci (CoNS) are responsible for a wide variety of human infections. The investigational antibacterial Debio1450 (previously AFN-1720), a prodrug of Debio1452 (previously AFN-1252), specifically targets staphylococci without significant activity against other Gram-pos. or Gram-neg. species. Debio1452 inhibits FabI, an enzyme crit. to fatty acid biosynthesis in staphylococci. The activity of Debio1452 against CoNS, methicillin-susceptible S. aureus (MSSA), and methicillin-resistant S. aureus (MRSA), including significant clones, was detd. A globally diverse collection of 574 patient isolates from 35 countries was tested that included CoNS (6 species, 103 strains), MSSA (154 strains), MRSA (163 strains), and molecularly characterized strains (including spa-typed MRSA clones; 154 strains). The isolates were tested for susceptibility by CLSI broth microdilution methods against Debio1452 and 10 comparators. The susceptibility rates for the comparators were detd. using CLSI and EUCAST breakpoint criteria. All S. aureus and CoNS strains were inhibited by Debio1452 concns. of ≤0.12 and ≤0.5 μg/mL, resp. The MIC50s for MSSA, MRSA, and molecularly characterized MRSA strains were 0.004 μg/mL, and the MIC90s ranged from 0.008 to 0.03 μg/mL. The MICs were higher for the CoNS isolates (MIC50/90, 0.015/0.12 μg/mL). Among S. aureus strains, resistance was common for erythromycin (61.6%), levofloxacin (49.0%), clindamycin (27.6%), tetracycline (15.7%), and trimethoprim-sulfamethoxazole (7.0%). Debio1452 demonstrated potent activity against MSSA, MRSA, and CoNS. Debio1452 showed significantly greater activity overall (MIC50, 0.004 μg/mL) than the other agents tested against these staphylococcal species, which included dominant MRSA clones and strains resistant to currently used antimicrobial agents.
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    45. 45
      Hafkin, B.; Kaplan, N.; Murphy, B. Efficacy and Safety of AFN-1252, the First Staphylococcus-Specific Antibacterial Agent, in the Treatment of Acute Bacterial Skin and Skin Structure Infections, Including Those in Patients with Significant Comorbidities. Antimicrob. Agents Chemother. 2016, 60 (3), 1695– 701,  DOI: 10.1128/AAC.01741-15
      44
      Efficacy and safety of AFN-1252, the first Staphylococcus-specific antibacterial agent, in the treatment of acute bacterial skin and skin structure infections, including those in patients with significant comorbidities
      Hafkin, B.; Kaplan, N.; Murphy, B.
      Antimicrobial Agents and Chemotherapy (2016), 60 (3), 1695-1701CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
      This open-label noncontrolled, phase II multicenter trial was designed to evaluate the safety, tolerability, and efficacy of 200 mg of AFN-1252, a selective inhibitor of Staphylococcus aureus enoyl-acyl carrier protein reductase (FabI), given by mouth twice daily in the treatment of acute bacterial skin and skin structure infections (ABSSSI) due to staphylococci. Important aspects of the current study included a comparison of early response efficacy endpoints with end-of-treatment and follow-up endpoints. Many patients in the intent-to-treat population (n = 103) had significant comorbidities. The overall early response rate at day 3 was 97.3% (wound, 100%; abscess, 96.6%; cellulitis, 94.4%) in the microbiol. evaluable (ME) population. Within the ME population, 82.9% of patients had a ≥ 20% decrease in the area of erythema, and 77.9% of patients had a ≥ 20% decrease in the area of induration, on day 3. S. aureus was detected in 97.7% of patients (n = 37 patients with methicillin-resistant S. aureus [MRSA], and n = 39 with methicillin-sensitive S. aureus [MSSA]). No isolates had increased AFN-1252 MICs posttreatment. Microbiol. eradication rates for S. aureus were 93.2% at short-term follow-up (STFU) and 91.9% at long-term follow-up (LTFU) in the ME population. Eradication rates for MRSA and MSSA were 91.9% and 92.3%, resp., at STFU and 91.9% and 89.7%, resp., at LTFU. The most frequently reported drug-related adverse events, which were mostly mild or moderate, were headache (26.2%) and nausea (21.4%). These studies demonstrate that AFN-1252 is generally well tolerated and effective in the treatment of ABSSSI due to S. aureus, including MRSA. This study has been registered at ClinicalTrials.gov under registration no.NCT01519492.
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    46. 46
      Radka, C. D.; Rock, C. O. Mining Fatty Acid Biosynthesis for New Antimicrobials. Annu. Rev. Microbiol. 2022, 76,  DOI: 10.1146/annurev-micro-041320-110408
      There is no corresponding record for this reference.
    47. 47
      Payne, D. J.; Warren, P. V.; Holmes, D. J.; Ji, Y.; Lonsdale, J. T. Bacterial fatty-acid biosynthesis: a genomics-driven target for antibacterial drug discovery. Drug Discov Today 2001, 6 (10), 537– 544,  DOI: 10.1016/S1359-6446(01)01774-3
      46
      Bacterial fatty-acid biosynthesis: a genomics-driven target for antibacterial drug discovery
      Payne, D. J.; Warren, P. V.; Holmes, D. J.; Ji, Y.; Lonsdale, J. T.
      Drug Discovery Today (2001), 6 (10), 537-544CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Science Ltd.)
      A review with 46 refs. demonstrating how the interplay of genomics, bioinformatics and genomic technologies has enabled an in-depth anal. of the component enzymes of the bacterial fatty-acid biosynthesis pathway as a source of novel antibacterial targets. This evaluation has revealed that many of the enzymes are potentially selective, broad-spectrum antibacterial targets. We also illustrate the suitability of some of these targets for HTS. Furthermore, we discuss how the availability of a robust selectivity assay, mode-of-action assays and numerous crystal structures provide an excellent set of tools with which to initiate integrated programs of research to identify novel antibiotics targeted at these enzymes.
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    48. 48
      Yao, J.; Rock, C. O. Bacterial fatty acid metabolism in modern antibiotic discovery. Biochim Biophys Acta Mol. Cell Biol. Lipids 2017, 1862 (11), 1300– 1309,  DOI: 10.1016/j.bbalip.2016.09.014
      47
      Bacterial fatty acid metabolism in modern antibiotic discovery
      Yao, Jiangwei; Rock, Charles O.
      Biochimica et Biophysica Acta, Molecular and Cell Biology of Lipids (2017), 1862 (11), 1300-1309CODEN: BBMLFG; ISSN:1388-1981. (Elsevier B.V.)
      Bacterial fatty acid synthesis is essential for many pathogens and different from the mammalian counterpart. These features make bacterial fatty acid synthesis a desirable target for antibiotic discovery. The structural divergence of the conserved enzymes and the presence of different isoenzymes catalyzing the same reactions in the pathway make bacterial fatty acid synthesis a narrow spectrum target rather than the traditional broad spectrum target. Furthermore, bacterial fatty acid synthesis inhibitors are single-targeting, rather than multi-targeting like traditional monotherapeutic, broad-spectrum antibiotics. The single-targeting nature of bacterial fatty acid synthesis inhibitors makes overcoming fast-developing, target-based resistance a necessary consideration for antibiotic development. Target-based resistance can be overcome through multi-targeting inhibitors, a cocktail of single-targeting inhibitors, or by making the single targeting inhibitor sufficiently high affinity through a pathogen selective approach such that target-based mutants are still susceptible to therapeutic concns. of drug. Many of the pathogens requiring new antibiotic treatment options encode for essential bacterial fatty acid synthesis enzymes. This review will evaluate the most promising targets in bacterial fatty acid metab. for antibiotic therapeutics development and review the potential and challenges in advancing each of these targets to the clinic and circumventing target-based resistance. This article is part of a Special Issue entitled: Bacterial Lipids edited by Russell E. Bishop.
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    49. 49
      Staley, C.; Vaughn, B. P.; Graiziger, C. T.; Sadowsky, M. J.; Khoruts, A. Gut-sparing treatment of urinary tract infection in patients at high risk of Clostridium difficile infection. J. Antimicrob. Chemother. 2017, 72 (2), 522– 528,  DOI: 10.1093/jac/dkw499
      48
      Gut-sparing treatment of urinary tract infection in patients at high risk of Clostridium difficile infection
      Staley, Christopher; Vaughn, Byron P.; Graiziger, Carolyn T.; Sadowsky, Michael J.; Khoruts, Alexander
      Journal of Antimicrobial Chemotherapy (2017), 72 (2), 522-528CODEN: JACHDX; ISSN:1460-2091. (Oxford University Press)
      Recipients of fecal microbiota transplantation (FMT) in treatment of recurrent Clostridium difficile infection (RCDI) remain at markedly increased risk of re-infection with C. difficile with new antibiotic provocations. Urinary tract infections (UTIs) are common indications for antibiotics in these patients, often resulting in C. difficile re-infection. We present a case series of 19 patients treated with parenteral aminoglycosides for UTI following FMT for RCDI. A 3 day outpatient regimen of once-daily i.m. administration of gentamicin was used to treat 18 consecutive FMT recipients with uncomplicated UTI. One other patient was treated for a complicated UTI with i.v. amikacin. Profiling of 16S rRNA genes was used to track changes in fecal microbial community structure during this regimen in three patients. The protocol was highly effective in treating UTI symptoms. None of the patients suffered a re-infection with C. difficile. The fecal microbial communities remained undisturbed by treatment with i.m. administration of gentamicin. Despite falling out of favor in recent years, aminoglycoside antibiotics given parenterally have the advantage of minimal penetration into the gut lumen. A brief (3 day) course of parenteral gentamicin was safe and effective in curing UTI in patients at high risk of C. difficile infection without perturbing their gut microbiota.
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    50. 50
      Worby, C. J.; Schreiber, H. L. t.; Straub, T. J.; van Dijk, L. R.; Bronson, R. A.; Olson, B. S.; Pinkner, J. S.; Obernuefemann, C. L. P.; Munoz, V. L.; Paharik, A. E.; Azimzadeh, P. N.; Walker, B. J.; Desjardins, C. A.; Chou, W. C.; Bergeron, K.; Chapman, S. B.; Klim, A.; Manson, A. L.; Hannan, T. J.; Hooton, T. M.; Kau, A. L.; Lai, H. H.; Dodson, K. W.; Hultgren, S. J.; Earl, A. M. Longitudinal multi-omics analyses link gut microbiome dysbiosis with recurrent urinary tract infections in women. Nat. Microbiol 2022, 7 (5), 630– 639,  DOI: 10.1038/s41564-022-01107-x
      49
      Longitudinal multi-omics analyses link gut microbiome dysbiosis with recurrent urinary tract infections in women
      Worby, Colin J.; Schreiber IV, Henry L.; Straub, Timothy J.; van Dijk, Lucas R.; Bronson, Ryan A.; Olson, Benjamin S.; Pinkner, Jerome S.; Obernuefemann, Chloe L. P.; Munoz, Vanessa L.; Paharik, Alexandra E.; Azimzadeh, Philippe N.; Walker, Bruce J.; Desjardins, Christopher A.; Chou, Wen-Chi; Bergeron, Karla; Chapman, Sinead B.; Klim, Aleksandra; Manson, Abigail L.; Hannan, Thomas J.; Hooton, Thomas M.; Kau, Andrew L.; Lai, H. Henry; Dodson, Karen W.; Hultgren, Scott J.; Earl, Ashlee M.
      Nature Microbiology (2022), 7 (5), 630-639CODEN: NMAICH; ISSN:2058-5276. (Nature Portfolio)
      Abstr.: Recurrent urinary tract infections (rUTIs) are a major health burden worldwide, with history of infection being a significant risk factor. While the gut is a known reservoir for uropathogenic bacteria, the role of the microbiota in rUTI remains unclear. We conducted a year-long study of women with (n = 15) and without (n = 16) history of rUTI, from whom we collected urine, blood and monthly faecal samples for metagenomic and transcriptomic interrogation. During the study 24 UTIs were reported, with addnl. samples collected during and after infection. The gut microbiome of individuals with a history of rUTI was significantly depleted in microbial richness and butyrate-producing bacteria compared with controls, reminiscent of other inflammatory conditions. However, Escherichia coli gut and bladder populations were comparable between cohorts in both relative abundance and phylogroup. Transcriptional anal. of peripheral blood mononuclear cells revealed expression profiles indicative of differential systemic immunity between cohorts. Altogether, these results suggest that rUTI susceptibility is in part mediated through the gut-bladder axis, comprising gut dysbiosis and differential immune response to bacterial bladder colonization, manifesting in symptoms.
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    51. 51
      Schembri, M. A.; Nhu, N. T. K.; Phan, M. D. Gut-bladder axis in recurrent UTI. Nat. Microbiol 2022, 7 (5), 601– 602,  DOI: 10.1038/s41564-022-01113-z
      50
      Gut-bladder axis in recurrent UTI
      Schembri, Mark A.; Nhu, Nguyen Thi Khanh; Phan, Minh-Duy
      Nature Microbiology (2022), 7 (5), 601-602CODEN: NMAICH; ISSN:2058-5276. (Nature Portfolio)
      Dysbiosis of the gut microbiome is assocd. with increased susceptibility to recurrent urinary tract infection, defining a gut-bladder axis.
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    52. 52
      Njoroge, M.; Kaur, G.; Espinoza-Moraga, M.; Wasuna, A.; Dziwornu, G. A.; Seldon, R.; Taylor, D.; Okombo, J.; Warner, D. F.; Chibale, K. Semisynthetic Antimycobacterial C-3 Silicate and C-3/C-21 Ester Derivatives of Fusidic Acid: Pharmacological Evaluation and Stability Studies in Liver Microsomes, Rat Plasma, and Mycobacterium tuberculosis culture. ACS Infect Dis 2019, 5 (9), 1634– 1644,  DOI: 10.1021/acsinfecdis.9b00208
      51
      Semisynthetic Antimycobacterial C-3 Silicate and C-3/C-21 Ester Derivatives of Fusidic Acid: Pharmacological Evaluation and Stability Studies in Liver Microsomes, Rat Plasma, and Mycobacterium tuberculosis culture
      Njoroge, Mathew; Kaur, Gurminder; Espinoza-Moraga, Marlene; Wasuna, Antonina; Dziwornu, Godwin Akpeko; Seldon, Ronnett; Taylor, Dale; Okombo, John; Warner, Digby F.; Chibale, Kelly
      ACS Infectious Diseases (2019), 5 (9), 1634-1644CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)
      Fusidic acid (FA), a natural product fusidane triterpene-based antibiotic with unique structural features, is active in vitro against Mycobacterium tuberculosis, the causative agent of tuberculosis (TB). While possessing good pharmacokinetics in man, FA is rapidly metabolized in rodents, thus complicating proof-of-concept studies in this model. Toward the repositioning of FA as an anti-TB agent, we herein describe the synthesis, activity, and metab. of FA and semisynthesized ester derivs. in rat liver microsomes, rat plasma, and mycobacterial cell culture. FA and deriv. mols. with a free C-3 OH underwent species-specific metab. to the corresponding 3-OH epimer, 3-epifusidic acid (3-epiFA). FA was also metabolized in rat plasma to form FA lactone. These addnl. routes of metab. may contribute to the more rapid clearance of FA obsd. in rodents. C-3 alkyl and aryl esters functioned as classic prodrugs of FA, being hydrolyzed to FA in microsomes, plasma, and Mycobacterium tuberculosis culture. In contrast, C-3 silicate esters and C-21 esters were inert to hydrolysis and so did not act as prodrugs. The antimycobacterial activity of the C-3 silicate esters was comparable to that of FA, and these compds. were stable in microsomes and plasma, identifying them as potential candidates for evaluation in a rodent model of tuberculosis.
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    53. 53
      Smith, P. W.; Zuccotto, F.; Bates, R. H.; Martinez-Martinez, M. S.; Read, K. D.; Peet, C.; Epemolu, O. Pharmacokinetics of beta-Lactam Antibiotics: Clues from the Past To Help Discover Long-Acting Oral Drugs in the Future. ACS Infect Dis 2018, 4 (10), 1439– 1447,  DOI: 10.1021/acsinfecdis.8b00160
      52
      Pharmacokinetics of β-Lactam Antibiotics: Clues from the Past To Help Discover Long-Acting Oral Drugs in the Future
      Smith, Paul W.; Zuccotto, Fabio; Bates, Robert H.; Martinez-Martinez, Maria Santos; Read, Kevin D.; Peet, Caroline; Epemolu, Ola
      ACS Infectious Diseases (2018), 4 (10), 1439-1447CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)
      A review. β-Lactams represent perhaps the most important class of antibiotics yet discovered. However, despite many years of active research, none of the currently approved drugs in this class combine oral activity with long duration of action. Recent developments suggest that new β-lactam antibiotics with such a profile would have utility in the treatment of tuberculosis. Consequently, the historical β-lactam pharmacokinetic data have been compiled and analyzed to identify possible directions and drug discovery strategies aimed toward new β-lactam antibiotics with this profile.
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