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Surface-Bound Antibiotic for the Detection of β-Lactamases
- Lisa M. Miller*Lisa M. Miller*E-mail: [email protected] (L.M.M.).Department of Chemistry, University of York, Heslington YO10 5DD, U.K.More by Lisa M. Miller
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- Callum D. SilverCallum D. SilverDepartment of Electronic Engineering, University of York, Heslington YO10 5DD, U.K.More by Callum D. Silver
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- Reyme HermanReyme HermanDepartment of Biology, University of York, Heslington YO10 5DD, U.K.More by Reyme Herman
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- Anne-Kathrin Duhme-KlairAnne-Kathrin Duhme-KlairDepartment of Chemistry, University of York, Heslington YO10 5DD, U.K.More by Anne-Kathrin Duhme-Klair
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- Gavin H. ThomasGavin H. ThomasDepartment of Biology, University of York, Heslington YO10 5DD, U.K.More by Gavin H. Thomas
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- Thomas F. KraussThomas F. KraussDepartment of Physics, University of York, Heslington YO10 5DD, U.K.More by Thomas F. Krauss
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- Steven D. Johnson*Steven D. Johnson*E-mail: [email protected] (S.D.J.).Department of Electronic Engineering, University of York, Heslington YO10 5DD, U.K.More by Steven D. Johnson
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Abstract
Antimicrobial resistance (AMR) has been identified as a major threat to public health worldwide. To ensure appropriate use of existing antibiotics, rapid and reliable tests of AMR are necessary. One of the most common and clinically important forms of bacterial resistance is to β-lactam antibiotics (e.g., penicillin). This resistance is often caused by β-lactamases, which hydrolyze β-lactam drugs, rendering them ineffective. Current methods for detecting these enzymes require either time-consuming growth assays or antibiotic mimics such as nitrocefin. Here, we report the development of a surface-bound, clinically relevant β-lactam drug that can be used to detect β-lactamases and that is compatible with a range of high-sensitivity, low-cost, and label-free analytical techniques currently being developed for point-of-care-diagnostics. Furthermore, we demonstrate the use of these functionalized surfaces to selectively detect β-lactamases in complex biological media, such as urine.
Introduction
ARTICLE SECTIONS
Antimicrobials are vital for the treatment and prevention of bacterial infections. However, infections that were once simple to remedy are becoming increasingly resistant to treatment. (1) Although the emergence of antimicrobial resistance (AMR) is inevitable through evolution of bacteria via natural selection, increased exposure as a result of the misuse and overuse of antibiotics has accelerated the development of AMR globally. (2,3) Conventional methods used to identify antimicrobial susceptibility can take days to complete and often require isolation and culturing of the pathogenic bacteria. (4) In order to preserve the efficacy of antimicrobial agents, it is imperative that the prescribing practice for antibiotics is improved by allowing clinicians to perform rapid and reliable tests of susceptibility. β-Lactam-based antimicrobials are one of the most commonly used classes of antibiotic. (5) As a defense against these drugs, many bacteria are able to produce enzymes that hydrolyze the drug’s pharmacophore (the β-lactam), rendering the drug inactive. Resistance to these classes of antibiotics is common, resulting in the restricted use of previously effective antibiotics, such as the earlier generations of penicillins. By detecting the presence (or absence) of β-lactamases, a susceptibility profile to these drugs can be deduced for a given infection and thus a suitable antibiotic can be prescribed. There are a number of methods currently available for the detection of β-lactamases, but these are limited to solution-phase assays. (6−11) A surface-based assay of β-lactam resistance would be compatible with a range of high-sensitivity, low-cost, and label-free analytical techniques developed for point-of-care diagnostics. (12−16)
Herein, we report the development of a surface-bound antibiotic able to respond to the presence of β-lactamases, which is compatible with the wide range of emerging surface-sensitive biosensing technologies. Hydrolysis of the surface-bound β-lactams by β-lactamases indicates resistance to the drug. Here, cephalexin (1) was identified as a suitable substrate for immobilization. This first-generation cephalosporin is used widely for the treatment of bacterial infections. (17) Furthermore, the amine present in the drug’s structure provides an ideal functional moiety for addition of a chemical tether (2), remote from the pharmacophore. This allows the compound to be anchored to a variety of surfaces, while minimizing the effect on the drug’s activity (Scheme 1). (18)
Scheme 1
Scheme 1. Design of the Surface-Bound Antibiotica
aSAM formation and attachment of cephalexin via a maleimide tether. For Au surfaces, X = SH; for SiO2 surfaces, X = Si(OEt)3. Inset: Structure of cephalexin (1) and cephalexin-R-maleimide (2), where R = CH2OCH2C(O)NHCH2PEG4CH2NHC(O)(CH2)5.
Results and Discussion
ARTICLE SECTIONS
A previous report has shown the preparation of a β-lactam-modified gold surface using a tether with a cyclic disulfide. (19) However, as many of the β-lactam antimicrobials feature a sulfur group within the core structure of the molecule, the orientation in which these molecules are bound to the surface remains ambiguous. (20) To ensure that the cephalexin molecules used here are immobilized on the surfaces in the optimal orientation, a two-step process was employed. Initially, the surface was modified with a self-assembled monolayer (SAM) with thiol terminal groups. The antibiotic was subsequently anchored to the thiolated surface via the maleimide tethered to the amine of cephalexin (2) (Scheme 1).
Ideally, the surface should enable β-lactamases to access the drug, hydrolyze the β-lactam, and then ultimately detach from the surface. A previously reported co-crystal structure of a β-lactamase bound to a β-lactam-based inhibitor was employed in the design of compound 2, to ensure that the tether was of sufficient length to distance the cephalexin from the surface and allow enzyme access (S1.1). (21) A polyethylene glycol (PEG) chain was chosen as these molecules are well known to inhibit physisorption of proteins onto surfaces, while providing conformational flexibility. (22,23) The thiol SAM was formed on an Au surface using 1,3-propanedithiol (Scheme 1). Control reactions confirmed that thiol addition was selective for the maleimide over the β-lactam (S1.7).
Polarization modulation infrared reflection adsorption spectroscopy (PM-IRRAS) allows direct chemical analysis of SAMs (24) and was employed here to confirm hydrolysis of this surface-bound antibiotic by β-lactamases. PM-IRRAS of a cephalexin-PEG functionalized Au surface revealed a band at around 1776 cm–1, consistent with the carbonyl of the β-lactam, confirming that the pharmacophore of the immobilized antibiotic remained intact (Figure 1). With a surface of cephalexin successfully prepared, the sample was immersed in a solution of potassium phosphate buffer (KPi) spiked with β-lactamases and incubated for 2 h to allow for the enzymes to hydrolyze the surface-bound cephalexin. PM-IRRAS showed the loss of the β-lactam carbonyl band, confirming that hydrolysis had occurred (Figure 1).
Figure 1
Figure 1. Structure of cephalexin-PEG-maleimide (2). PM-IRRAS spectra of the cephalexin-PEG surface before (red) and after (blue) exposure to β-lactamases.
Control reactions demonstrated the stability of the surface-bound drug in the absence of β-lactamases, verifying that hydrolysis was a result of the enzyme-catalyzed reaction (S3.1 IR08). Whereas PM-IRRAS confirmed that β-lactamases were able to hydrolyze the immobilized cephalexin, IR absorption in the amide I band region (1666 cm–1) indicated that protein fouling of the surface was occurring.
Quartz crystal microbalance with dissipation (QCM-D) monitoring was employed to further study the surface-bound drug, enabling quantification of the surface concentration of proteins and other molecules [calculated using the Sauerbrey equation (S3.2)]. For clarity, the frequency data are discussed herein, with dissipation data included in the Supporting Information (S3.3.). To explore the versatility of the surface-bound antibiotic, we investigated two different QCM-D sensors coated with Au or SiO2. Cephalexin-PEG (2) was immobilized on the Au-coated sensors via a thiol SAM formed using 1,3-propanedithiol. The surface chemistry was adapted for the SiO2 sensors using 3-mercaptopropyltriethoxysilane (MPTES) to thiolate the surface. The surface concentration of cephalexin-PEG (2) was found to be comparable on both the Au- and SiO2-coated sensors (Figure 2). Both coatings were calculated to have approximately 1.77 × 1014 molecules/cm2 (typical for a PEG monolayer) (25,26) of cephalexin-PEG (2) bound, demonstrating the generality of the surface chemistry.
Figure 2
Figure 2. QCM-D experiment monitoring cephalexin-PEG (2) binding to the thiolated surfaces of SiO2 and Au sensors. The introduction of each solution is indicated by labeled arrows and dashed lines.
The two surfaces (Au and SiO2) were studied further to examine the interaction of β-lactamases with the surface-bound antibiotics. We found that physisorbed β-lactamases could be effectively removed from both the Au and SiO2 surfaces functionalized with cephalexin-PEG (2) by washing with a 2% sodium dodecyl sulfate (SDS) solution (S3.3 QCM02). Complementary experiments using a cephalexin analogue with a short alkane tether showed increased biofouling, confirming the effectiveness of the PEG linker in minimizing protein physisorption (S3.3 QCM02). We note that the cephalexin-PEG monolayer was found to be stable following exposure to 2% SDS (S3.1 IR08). Additional QCM-D analyses (discussed below) were performed using both Au and SiO2 sensors to demonstrate the versatility of the surface-bound antibiotic. For clarity, the Au data are discussed herein, with data for the SiO2 surfaces included in the Supporting Information (S3.3).
As the drug–enzyme complex is short-lived and there is no significant change in mass of the surface-bound drug after β-lactam hydrolysis, a suitable probe is required to confirm the hydrolysis reaction when using QCM-D. A penicillin-binding protein (PBP), the therapeutic target for β-lactam antibiotics, was chosen as it binds covalently to the active site of the protein. Because of the specificity of this protein, it allows for detection of the orientation and state of the surface-bound β-lactam (Figure 3a). Suitability of this probe was confirmed using a set of experiments in which three QCM-D sensors were functionalized with cephalexin-PEG (2). One sensor was exposed to PBP, the second was challenged with PBP which had been pre-incubated with cephalexin (1) to block the binding site, thus deactivating it, while the third was pre-exposed to 1 M NaOH in order to chemically hydrolyze the β-lactams. All sensors were then washed using a 2% SDS solution in order to remove noncovalently bound PBPs.
Figure 3
Figure 3. (a) Use of PBP as a probe for QCM-D studies. (b) QCM-D experiment of surface-bound cephalexin-PEG (2) on Au: (1) PBP only; (2) PBP preincubated with cephalexin; (3) surface antibiotics pre-treated with NaOH, a gap in the data indicates a skipped buffer step. The introduction of each solution is shown by labeled arrows and dashed lines. The number of PBPs bound after the final wash is shown for each sensor. Data reported as mean value ± standard deviation.
A significant shift in resonant frequency was observed only when both the β-lactam was intact and the PBP was active (Figure 3b). The average value of this frequency shift (−27 Hz) suggests that approximately 1 × 1013 PBPs/cm2 are covalently bound to intact β-lactams on the surface. This surface density is typical of a protein monolayer, (27) suggesting that around 7% of surface-immobilized cephalexin molecules are bound to PBPs. This experiment confirmed the suitability of PBPs as a probe for the intact β-lactams. We note that when the PBPs were covalently bound to the surface-bound antibiotics, a large shift in frequency was observed following the introduction of SDS (Figure 3b(1)). Because of the covalent nature of the protein–drug bond, the surfactant interacts with the PBPs, but is unable to remove the proteins from the surface, causing a build-up of surfactant and a concomitant increase in mass.
Having confirmed that a PBP can function as a suitable probe for β-lactam hydrolysis, additional measurements were performed to further confirm the activity of β-lactamases against the cephalexin-PEG surface. As reported, a significant shift in frequency was observed following exposure of a cephalexin-PEG surface to PBPs. In contrast, a significantly lower concentration of PBPs (5.7 × 1012 PBPs/cm2) was observed after the cephalexin-PEG surface was first challenged with β-lactamases (Figure 4). It was also noted that the frequency spike associated with the SDS wash was much reduced for the sensor exposed to β-lactamases, indicating that PBPs physisorb rather than covalently bind to the surface. Control measurements using a β-lactamase inhibitor confirmed that the reduction in PBP binding was a result of β-lactam hydrolysis, rather than nonspecific adsorption of the β-lactamases blocking the surface (S3.3 QCM07/08). These results combined with the PM-IRRAS data (Figure 1) confirm that β-lactamases are capable of hydrolyzing the surface-bound antibiotics.
Figure 4
Figure 4. QCM-D experiment of surface-bound cephalexin-PEG (2) on Au: (1) PBPs only and (2) β-lactamases followed by PBPs. The introduction of each solution is shown by labeled arrows and dashed lines. The number of PBPs bound after the final wash is shown for each sensor. Data reported as mean value ± standard deviation.
A stage often neglected in the development of novel biosensors is the compatibility of the device, and thus the sensor surface, with clinical samples. However, in order for rapid testing to be a possibility, tests should ideally be performed directly on clinical samples. (28) To this end, we explored the robustness of the cephalexin-PEG surface for the detection of β-lactamases in physiological samples, specifically urine. Urine is analyzed routinely for diagnosis and susceptibility testing of urinary tract infections but, as a complex biological medium, it contains intact human cells, proteins, and small molecules creating a challenge for in-matrix detection. Gold samples were prepared with cephalexin-PEG (2) for analysis by PM-IRRAS. These samples were then exposed to urine spiked with β-lactamases or, as a control, challenged with urine only. Both surfaces showed excellent selectivity in response to β-lactamases, with reduction in the β-lactam carbonyl band only being observed in the samples exposed to urine spiked with β-lactamases (Figure 5a). The preservation of the β-lactams in the control samples (i.e., without β-lactamases, Figure 5b) demonstrates the stability of the surface-bound drug in urine over an extended time period. We note that hydrolysis of the β-lactam was incomplete after 24 h. In contrast, experiments performed using β-lactamases in buffer (Figure 1) showed loss of the β-lactam carbonyl band after 2 h. It is likely that the high protein concentration of urine resulted in increased surface biofouling, evidenced by a large IR band with maximum absorbance at 1664 cm–1, which could inhibit access to the surface-bound drug, thus inhibiting complete hydrolysis.
Figure 5
Figure 5. PM-IRRAS and QCM-D studies in urine. (a) PM-IRRAS test: before and after exposure to urine spiked with β-lactamases. (b) PM-IRRAS control: before and after exposure to urine only. (c) QCM-D experiment of surface-bound cephalexin-PEG (2) on Au: (1) urine only and (2) urine spiked with β-lactamases. The introduction of each solution is shown by labeled arrows and dashed lines. The number of PBPs bound after the final wash is shown for each sensor. Data reported as mean value ± standard deviation.
Complementary experiments were performed using QCM-D. The cephalexin-PEG monolayer, assembled on Au-coated QCM-D sensors, was exposed either to urine spiked with β-lactamases or to urine only. All sensors were washed in flow during the QCM-D measurement to ensure that each sample was treated to the same washing procedures, allowing a consistent baseline to be established (S3.3 QCM09/10). Significantly more binding of PBPs was observed on surfaces that had not previously been exposed to β-lactamases (Figure 5c). Comparing the urine studies (Figure 5c) to previous QCM-D experiments performed in buffer (Figure 4), it is clear that the number of PBPs binding to the cephalexin-PEG exposed to urine was reduced. This reduction in binding is likely due to the large number of nontarget proteins in urine; however, the surface still provides a robust and detectable response despite these challenging conditions.
Conclusions
ARTICLE SECTIONS
In conclusion, this work details the development of a surface-bound antibiotic, able to detect the presence of β-lactamases in urine. Studies using PM-IRRAS and QCM-D demonstrated the successful hydrolysis of the surface-bound drugs by β-lactamases and confirmed the stability of the drug surface in the absence of these enzymes, even in urine. Results obtained from the antibiotic-functionalized Au and SiO2 surfaces were comparable, demonstrating the versatility of this method. This versatility could be exploited to allow integration of our novel cephalexin-PEG (2) with a wide range of current and emerging surface affinity biosensor technologies that ultimately could provide evidence-based diagnostics for the rational and targeted prescription of antibiotics.
Materials and Methods
ARTICLE SECTIONS
Compound Synthesis
Details of the synthetic procedures, compound characterization, and spectra are provided in the Supporting Information (S1).
Materials
Planar gold surfaces were prepared for studies using PM-IRRAS. Briefly, samples were fabricated by electron beam evaporation of 25 nm Ti/100 nm Au onto cleaned Si wafers purchased from IDB Technologies. Gold (QSX 301)- and silicon dioxide (QSX 303)-coated QCM-D sensors were purchased from Biolin Scientific. Unless otherwise stated, solvents and reagents purchased commercially were used without further purification. 1,3-Propanedithiol was purchased from Sigma-Aldrich and MPTES was purchased from TCI Chemicals. DMSO was purchased from Fisher Scientific.
Instrumentation
PM-IRRAS spectra were acquired using a Bruker Vertex 70 spectrometer coupled with a PMA50 polarization modulation unit (Hinds Instruments, Oregon, USA). QCM-D spectra were recorded on a QSense E4, QFM 401. The surface area exposed to solution was equal to 0.95 cm2 as defined by a Viton O-ring. The temperature in the QCM-D chamber was controlled by a Peltier device and was set to 37 °C (standard deviation 5 × 10–3 °C) for all measurements.
Surface Functionalization
Gold wafers for PM-IRRAS were cleaned by immersion in piranha solution (H2SO4/H2O2 70:30) for 10 min, followed by sonication in water and ethanol for 10 min each. QCM-D sensors were cleaned by UV–ozone treatment (10 min), followed by sonication in a 2% Hellmanex III solution (Hellma Analytics, Müllheim, Germany) (10 min) and then sonication in ultrapure water (2 × 10 min), followed by UV–ozone treatment (30 min) and immersion in EtOH (30 min). Cleaned samples were functionalized according to the type of surface employed. Cleaned gold samples were functionalized with 1,3-propanedithiol by 24 h immersion in a 10 μM MeOH solution. However, cleaned silicon dioxide samples were functionalized with MPTES by 24 h immersion in 4% v/v MPTES/IPA solution. Following the formation of the thiol SAM, samples were gently rinsed with ultrapure water and dried with N2 gas. The samples were then immersed in the required cephalexin-maleimide analogue solution (2 μM in 25% DMSO/H2O) for 24 h to allow formation of the thiol–maleimide conjugate. Finally, the samples were gently rinsed with 50% DMSO/H2O followed by ultrapure water, then dried with N2 gas.
β-Lactamase Stock Solution
A blend of recombinant β-lactamase proteins, expressed in Escherichia coli, was purchased from Sigma-Aldrich (L7920) and used without further purification. The lyophilized powder was dissolved in 50 mM KPi (pH 7) and aliquoted into 1 mL aliquots, each containing 40–70 IU β-lactamase I and 6–10 IU β-lactamase II. The enzyme stock solutions were stored below 0 °C. For experiments testing the hydrolysis by β-lactamase, stock enzyme solution was diluted ×6 in the required test solution. Concentrations were maintained at this dilution throughout all experiments.
Expression and Purification of PBP
A truncated version of the ftsI gene formed of residues W44-S588, encoding only the soluble domain, was amplified from E. coli BW25113. The resulting construct was inserted into the vector pBADnLIC2005, (29) introducing an N-terminal deca-histidine tag when expressed. The resulting vector was transformed into E. coli MC1061 for expression. Cultures for protein expression were grown in 1 L of Luria-Bertani broth at 37 °C on an orbital shaker. Expression was induced by addition of 0.01% l-arabinose during mid-log phase of growth. Cultures were further incubated for 4 h and cells were harvested by centrifugation. Cell pellets were resuspended in 50 mM KPi pH 7.8, 200 mM NaCl, 10 mM imidazole, 20% glycerol with 1 mM phenylmethylsulfonyl fluoride followed by sonication. The lysate was clarified by centrifugation before loading onto a HisTrap HF column (GE Healthcare). To remove any pre-bound ligands, refolding purification was performed by initially washing with the protein unfolding buffer [2 M guanidine HCl, 50 mM KPi (pH 7.8), 200 mM NaCl, 20% glycerol, and 20 mM imidazole] and then performing a gradient wash to the protein refolding buffer [50 mM KPi (pH 7.8), 200 mM NaCl, 20% glycerol, and 20 mM imidazole] before the elution of the protein using the elution buffer [50 mM KPi (pH 7.8), 200 mM NaCl, 20% glycerol, and 500 mM imidazole]. The eluted protein was buffer-exchanged to the buffer 50 mM KPi (pH 7.8), 200 mM NaCl using a HiTrap Desalting (GE Healthcare) column. Binding activity of the purified E. coli PBP3 was confirmed using a thermal shift assay; details can be found in the Supporting Information (S2).
PBP Stock Solution
Protein concentration was determined using the Beer–Lambert law from the absorbance at 280 nm with an extinction coefficient of 58 790 M–1 cm–1. For surface experiments using PBP, solutions were prepared to 1 μM protein in 50 mM KPi (pH 7).
Urine Samples
Urine samples were collected anonymously from 13 healthy adults that had not shown symptoms of infection or taking antibiotics within 1 month prior to the sample collection. Participants were recruited from within the University of York. Samples were filter-sterilized using 0.22 μm syringe filters to remove any cells. The urine samples were combined to form an “average” human urine, which was aliquoted and stored in a −80 °C freezer. The pH of the resulting urine was measured to be pH 6.7. Control experiments did not detect any β-lactamases within the urine stock (S1.8).
PM-IRRAS Surface Studies
Following formation of the functionalized surfaces, the gold wafers were immersed in the test solution as described in the experimental procedures (Supporting Information). Once the surface reactions were complete, the gold wafers were cleaned according to the procedure detailed in the Supporting Information and then loaded into the PM-IRRAS spectrometer. The incident angle was set at 80° with a 4 cm–1 spectral resolution, while the PEM controller operated at 2000 cm–1. Average measurement time was 15 min, collecting 1000 scans. Spectra and experimental details of each sample analyzed are provided in the Supporting Information (S3.1).
QCM-D Surface Studies
Following formation of the functionalized surfaces, each sensor was then installed into the flow modules of the Q-Sense E4 system. Each chamber was then filled with Milli-Q water at a flow rate of 100 μL/min controlled by a four-channel peristaltic pump. To achieve a stable baseline, the running buffer was left to flow through the modules at 20 μL/min for 60–80 min until the drift in frequency was <±1 Hz over 10 min. For all experiments, the temperature of the modules was kept at 37 °C (standard deviation 5 × 10–3 °C) and the flow rate was kept constant at 20 μL/min. Buffer was allowed to flow over the sensor surface between sample injections until a stable level was achieved, corresponding to a drift in frequency <±1 Hz over 10 min. QCM-D spectra showing both the frequency and dissipation shifts for each experiment, with noteworthy shifts in frequency being indicated by shaded horizontal bars, are provided in the Supporting Information (S3.3). Surface concentrations of proteins were calculated using the Sauerbrey equation (S3.2). We accept that this method of analysis assumes a thin, rigid, and uniform layer, and is therefore only an estimated value.
Supporting Information
ARTICLE SECTIONS
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsami.9b05793.
Compound synthesis and characterization, protein binding assay, PM-IRRAS, and additional QCM-D data (PDF)
Terms & Conditions
Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.
Author Information
ARTICLE SECTIONS
- Lisa M. Miller - Department of Chemistry, , , and , University of York, Heslington YO10 5DD, U.K.;
http://orcid.org/0000-0003-3667-3840;
- Gavin H. Thomas - Department of Biology, , , and , University of York, Heslington YO10 5DD, U.K.;http://orcid.org/0000-0002-9763-1313
Acknowledgments
ARTICLE SECTIONS
We thank EPSRC for funding (EP/P02324X/1 and EP/P030017/1). We thank Stephen Thorpe for his work in attaining ethical approval for the collection and preparation of urine samples. We thank Heather Fish for her assistance in obtaining NMR spectra.
| AMR | antimicrobial resistance |
| KPi | potassium phosphate buffer |
| MPTES | 3-mercaptopropyltriethoxysilane |
| PBP | penicillin binding protein |
| PEG | polyethylene glycol |
| PM-IRRAS | polarization modulation infrared reflection adsorption spectroscopy |
| QCM-D | quartz crystal microbalance with dissipation |
| SAM | self-assembled monolayer |
References
ARTICLE SECTIONS
This article references 29 other publications.
- 1Sultan, I.; Rahman, S.; Jan, A. T.; Siddiqui, M. T.; Mondal, A. H.; Haq, Q. M. R. Antibiotics, Resistome and Resistance Mechanisms: A Bacterial Perspective. Front. Microbiol. 2018, 9, 2066, DOI: 10.3389/fmicb.2018.02066Google Scholar1https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3czntVCiuw%253D%253D&md5=3eaa839bd598f33b4b1262b56c16173eAntibiotics, Resistome and Resistance Mechanisms: A Bacterial PerspectiveSultan Insha; Siddiqui Mohammad Tahir; Mondal Aftab Hossain; Haq Qazi Mohd Rizwanul; Rahman Safikur; Jan Arif TasleemFrontiers in microbiology (2018), 9 (), 2066 ISSN:1664-302X.History of mankind is regarded as struggle against infectious diseases. Rather than observing the withering away of bacterial diseases, antibiotic resistance has emerged as a serious global health concern. Medium of antibiotic resistance in bacteria varies greatly and comprises of target protection, target substitution, antibiotic detoxification and block of intracellular antibiotic accumulation. Further aggravation to prevailing situation arose on observing bacteria gradually becoming resistant to different classes of antibiotics through acquisition of resistance genes from same and different genera of bacteria. Attributing bacteria with feature of better adaptability, dispersal of antibiotic resistance genes to minimize effects of antibiotics by various means including horizontal gene transfer (conjugation, transformation, and transduction), Mobile genetic elements (plasmids, transposons, insertion sequences, integrons, and integrative-conjugative elements) and bacterial toxin-antitoxin system led to speedy bloom of antibiotic resistance amongst bacteria. Proficiency of bacteria to obtain resistance genes generated an unpleasant situation; a grave, but a lot unacknowledged, feature of resistance gene transfer.
- 2Davies, J.; Davies, D. Origins and Evolution of Antibiotic Resistance. Microbiol. Mol. Biol. Rev. 2010, 74, 417– 433, DOI: 10.1128/mmbr.00016-10Google Scholar2https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVSqurnO&md5=64214f42f2ae91c1ba94dbe765b7cd0cOrigins and evolution of antibiotic resistanceDavies, Julian; Davies, DorothyMicrobiology and Molecular Biology Reviews (2010), 74 (3), 417-433CODEN: MMBRF7; ISSN:1092-2172. (American Society for Microbiology)A review. Antibiotics have always been considered one of the wonder discoveries of the 20th century. This is true, but the real wonder is the rise of antibiotic resistance in hospitals, communities, and the environment concomitant with their use. The extraordinary genetic capacities of microbes have benefitted from man's overuse of antibiotics to exploit every source of resistance genes and every means of horizontal gene transmission to develop multiple mechanisms of resistance for each and every antibiotic introduced into practice clin., agriculturally, or otherwise. This review presents the salient aspects of antibiotic resistance development over the past half-century, with the oft-restated conclusion that it is time to act. To achieve complete restitution of therapeutic applications of antibiotics, there is a need for more information on the role of environmental microbiomes in the rise of antibiotic resistance. In particular, creative approaches to the discovery of novel antibiotics and their expedited and controlled introduction to therapy are obligatory.
- 3Klein, E. Y.; Van Boeckel, T. P.; Martinez, E. M.; Pant, S.; Gandra, S.; Levin, S. A.; Goossens, H.; Laxminarayan, R. Global Increase and Geographic Convergence in Antibiotic Consumption Between 2000 and 2015. Proc. Natl. Acad. Sci. U.S.A. 2018, 115, E3463– E3470, DOI: 10.1073/pnas.1817182115Google Scholar3https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXht1Gqt7jM&md5=7888300662d6de00d91a7b5c26844657Global increase and geographic convergence in antibiotic consumption between 2000 and 2015Klein, Eili Y.; Boeckel, Thomas P. Van; Martinez, Elena M.; Pant, Suraj; Gandra, Sumanth; Levin, Simon A.; Goossens, Herman; Laxminarayan, RamananProceedings of the National Academy of Sciences of the United States of America (2018), 115 (15), E3463-E3470CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Tracking antibiotic consumption patterns over time and across countries could inform policies to optimize antibiotic prescribing and minimize antibiotic resistance, such as setting and enforcing per capita consumption targets or aiding investments in alternatives to antibiotics. In this study, we analyzed the trends and drivers of antibiotic consumption from 2000 to 2015 in 76 countries and projected total global antibiotic consumption through 2030. Between 2000 and 2015, antibiotic consumption, expressed in defined daily doses (DDD), increased 65% (21.1-34.8 billion DDDs), and the antibiotic consumption rate increased 39% (11.3-15.7 DDDs per 1,000 inhabitants per day). The increase was driven by low- and middle-income countries (LMICs), where rising consumption was correlated with gross domestic product per capita (GDPPC) growth (P = 0.004). In high-income countries (HICs), although overall consumption increased modestly, DDDs per 1,000 inhabitants per day fell 4%, and there was no correlation with GDPPC. Of particular concern was the rapid increase in the use of last-resort compds., both in HICs and LMICs, such as glycylcyclines, oxazolidinones, carbapenems, and polymyxins. Projections of global antibiotic consumption in 2030, assuming no policy changes, were up to 200% higher than the 42 billion DDDs estd. in 2015. Although antibiotic consumption rates in most LMICs remain lower than in HICs despite higher bacterial disease burden, consumption in LMICs is rapidly converging to rates similar to HICs. Reducing global consumption is crit. for reducing the threat of antibiotic resistance, but redn. efforts must balance access limitations in LMICs and take account of local and global resistance patterns.
- 4Syal, K.; Mo, M.; Yu, H.; Iriya, R.; Jing, W.; Guodong, S.; Wang, S.; Grys, T. E.; Haydel, S. E.; Tao, N. Current and Emerging Techniques for Antibiotic Susceptibility Tests. Theranostics 2017, 7, 1795– 1805, DOI: 10.7150/thno.19217Google Scholar4https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvFyju7%252FL&md5=65c2f5678447e904d99d0406267f48aeCurrent and emerging techniques for antibiotic susceptibility testsSyal, Karan; Mo, Manni; Yu, Hui; Iriya, Rafael; Jing, Wenwen; Guodong, Sui; Wang, Shaopeng; Grys, Thomas E.; Haydel, Shelley E.; Tao, NongjianTheranostics (2017), 7 (7), 1795-1805CODEN: THERDS; ISSN:1838-7640. (Ivyspring International Publisher)Infectious diseases caused by bacterial pathogens are a worldwide burden. Serious bacterial infection-related complications, such as sepsis, affect over a million people every year with mortality rates ranging from 30% to 50%. Crucial clin. microbiol. lab. responsibilities assocd. with patient management and treatment include isolating and identifying the causative bacterium and performing antibiotic susceptibility tests (ASTs), which are labor-intensive, complex, imprecise, and slow (taking days, depending on the growth rate of the pathogen). Considering the life-threatening condition of a septic patient and the increasing prevalence of antibiotic-resistant bacteria in hospitals, rapid and automated diagnostic tools are needed. This review summarizes the existing com. AST methods and discusses some of the promising emerging AST tools that will empower humans to win the evolutionary war between microbial genes and human wits.
- 5Kresse, H.; Belsey, M. J.; Rovini, H. The Antibacterial Drugs Market. Nat. Rev. Drug Discovery 2007, 6, 19– 20, DOI: 10.1038/nrd2226Google Scholar5https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtlGktbfJ&md5=4461c36146026ffa85b1db0d3ea51a6fThe antibacterial drugs marketKresse, Hedwig; Belsey, Mark J.; Rovini, HolgerNature Reviews Drug Discovery (2007), 6 (1), 19-20CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)There is no expanded citation for this reference.
- 6O’Callaghan, C. H.; Morris, A.; Kirby, S. M.; Shingler, A. H. Novel Method for Detection of β-Lactamases by Using a Chromogenic Cephalosporin Substrate. Antimicrob. Agents Chemother. 1972, 1, 283– 288, DOI: 10.1128/aac.1.4.283Google Scholar6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaE2c7ns1agsg%253D%253D&md5=dc646a87f692cf4413e81d22218da743Novel method for detection of beta-lactamases by using a chromogenic cephalosporin substrateO'Callaghan C H; Morris A; Kirby S M; Shingler A HAntimicrobial agents and chemotherapy (1972), 1 (4), 283-8 ISSN:0066-4804.A new cephalosporin with a highly reactive beta-lactam ring was found to give an immediate color change in the presence of beta-lactamases from many bacteria, including staphylococci, Bacillus species, Enterobacteriaceae, and Pseudomonas. The reaction is confined to organisms producing beta-lactamases, but it is sufficiently sensitive to indicate the presence of this enzyme is small amounts in strains previously considered not to produce it. The compound has an unusual ultraviolet spectrum, and the color change can be followed quantitatively by measuring changes in absorption which occur in the 380- to 500-nm region, where cephalosporins normally have no absorption. The development of color is thought to be a consequence of the beta-lactam ring being unusually highly conjugated with the 3-substituent. Although in the bacteria only beta-lactamases produce this color change, it was found that serum and tissues from experimental animals also rapidly produced the colored breakdown product, which was then excreted in the urine. The mechanism of the mammalian breakdown was considered to be different from that found in bacteria.
- 7deBoer, T. R.; Tarlton, N. J.; Yamaji, R.; Adams-Sapper, S.; Wu, T. Z.; Maity, S.; Vesgesna, G. K.; Sadlowski, C. M.; DePaola, P.; Riley, L. W.; Murthy, N. An Enzyme-Mediated Amplification Strategy Enables Detection of β-Lactamase Activity Directly in Unprocessed Clinical Samples for Phenotypic Detection of β-Lactam Resistance. ChemBioChem 2018, 19, 2173– 2177, DOI: 10.1002/cbic.201800443Google Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslyrtLjJ&md5=ccde5b311030bd1f1ced7ab4b2cecb90An Enzyme-Mediated Amplification Strategy Enables Detection of β-Lactamase Activity Directly in Unprocessed Clinical Samples for Phenotypic Detection of β-Lactam ResistancedeBoer, Tara R.; Tarlton, Nicole J.; Yamaji, Reina; Adams-Sapper, Sheila; Wu, Tiffany Z.; Maity, Santanu; Vesgesna, Giri K.; Sadlowski, Corinne M.; DePaola, Peter, IV; Riley, Lee W.; Murthy, NirenChemBioChem (2018), 19 (20), 2173-2177CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)Biochem. assays that can identify β-lactamase activity directly from patient samples have the potential to significantly improve the treatment of bacterial infections. However, current β-lactamase probes do not have the sensitivity needed to measure β-lactam resistance directly from patient samples. Here, we report the development of an instrument-free signal amplification technol., DETECT, that connects the activity of two enzymes in series to effectively amplify the activity of β-lactamase 40 000-fold, compared to the std. β-lactamase probe nitrocefin.
- 8Gallah, S.; Decre, D.; Genel, N.; Arlet, G. The -Lacta Test for Direct Detection of Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae in Urine. J. Clin. Microbiol. 2014, 52, 3792– 3794, DOI: 10.1128/jcm.01629-14Google Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cbnsVeltw%253D%253D&md5=8190438087e996cd2d3fea0a990f5dffThe β-Lacta test for direct detection of extended-spectrum-β-lactamase-producing Enterobacteriaceae in urineGallah Salah; Decre Dominique; Genel Nathalie; Arlet GuillaumeJournal of clinical microbiology (2014), 52 (10), 3792-4 ISSN:.With the β-Lacta test, production of extended-spectrum β-lactamases (ESBLs) was assayed in 200 urine samples showing Gram-negative bacilli during direct microscopic examination. While 168 samples tested negative, all samples yielding ESBL-producing Enterobacteriaceae after culture gave positive (n = 30) or uninterpretable (n = 2) results. The sensitivity and specificity of ESBL detection were 94% and 100%, respectively.
- 9Yao, H.; So, M.-k.; Rao, J. A Bioluminogenic Substrate for In Vivo Imaging of β-Lactamase Activity. Angew. Chem., Int. Ed. 2007, 46, 7031– 7034, DOI: 10.1002/anie.200701931Google Scholar9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFSqtL%252FO&md5=90e2abf229bbd429e375d501bb8b0c2dA bioluminogenic substrate for in vivo imaging of β-lactamase activityYao, Hequan; So, Min-Kyung; Rao, JianghongAngewandte Chemie, International Edition (2007), 46 (37), 7031-7034CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A caged β-lactam-D-luciferin (Bluco) conjugate can image β-lactamase activity in vivo through a two-step enzymic process. This novel bioluminogenic probe should facilitate the detection of β-lactamase and widen its applications as a reporter.
- 10Zlokarnik, G.; Negulescu, P. A.; Knapp, T. E.; Mere, L.; Burres, N.; Feng, L.; Whitney, M.; Roemer, K.; Tsien, R. Y. Quantitation of Transcription and Clonal Selection of Single Living Cells with β-Lactamase as Reporter. Science 1998, 279, 84– 88, DOI: 10.1126/science.279.5347.84Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXjtVSjsg%253D%253D&md5=25d3beee86614403847e2ec7b26aed18Quantitation of transcription and clonal selection of single living cells with β-lactamase as reporterZlokarnik, Gregor; Negulescu, Paul A.; Knapp, Thomas E.; Mere, Lora; Burres, Neal; Feng, Luxin; Whitney, Michael; Roemer, Klaus; Tsien, Roger Y.Science (Washington, D. C.) (1998), 279 (5347), 84-88CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Gene expression was visualized in single living mammalian cells with β-lactamase as a reporter that hydrolyzes a substrate loaded intracellularly as a membrane-permeant ester. Each enzyme mol. changed the fluorescence of many substrate mols. from green to blue by disrupting resonance energy transfer. This wavelength shift was detectable by eye or color film in individual cells contg. less than 100 β-lactamase mols. The robust change in emission ratio reveals quant. heterogeneity in real-time gene expression, enables clonal selection by flow cytometry, and forms a basis for high-throughput screening of pharmaceutical candidate drugs in living mammalian cells.
- 11Gao, W.; Xing, B.; Tsien, R. Y.; Rao, J. Novel Fluorogenic Substrates for Imaging β-Lactamase Gene Expression. J. Am. Chem. Soc. 2003, 125, 11146– 11147, DOI: 10.1021/ja036126oGoogle Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXmsVelsrk%253D&md5=3ff7d10e2798d1adb0174414da8cb98dNovel Fluorogenic Substrates for Imaging β-Lactamase Gene ExpressionGao, Wenzhong; Xing, Bengang; Tsien, Roger Y.; Rao, JianghongJournal of the American Chemical Society (2003), 125 (37), 11146-11147CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)A new class of small nonfluorescent fluorogenic substrates, based on release of a phenolic dye from a vinylogous cephalosporin, becomes brightly fluorescent after β-lactamase hydrolysis with up to 153-fold enhancement in the fluorescence intensity. Less than 500 fM of β-lactamase in cell lysates can be readily detected, and β-lactamase expression in living cells can be imaged with a red fluorescence deriv. These new fluorogenic substrates should find uses in clin. diagnostics and facilitate the applications of β-lactamase as a biosensor.
- 12Wongkaew, N.; Simsek, M.; Griesche, C.; Baeumner, A. J. Functional Nanomaterials and Nanostructures Enhancing Electrochemical Biosensors and Lab-on-a-Chip Performances: Recent Progress, Applications, and Future Perspective. Chem. Rev. 2019, 119, 120– 194, DOI: 10.1021/acs.chemrev.8b00172Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslKis7nO&md5=a799268cbf763f6e9ebef46c5b6db2c7Functional Nanomaterials and Nanostructures Enhancing Electrochemical Biosensors and Lab-on-a-Chip Performances: Recent Progress, Applications, and Future PerspectiveWongkaew, Nongnoot; Simsek, Marcel; Griesche, Christian; Baeumner, Antje J.Chemical Reviews (Washington, DC, United States) (2019), 119 (1), 120-194CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. Electrochem. biosensors and assocd. lab-on-a-chip devices are the anal. system of choice when rapid and on-site results are needed in medical diagnostics and food safety, for environmental protection, process control, wastewater treatment, and life sciences discovery research among many others. A premier example is the glucose sensor used by diabetic patients. Current research focuses on developing sensors for specific analytes in these application fields and addresses challenges that need to be solved before viable com. products can be designed. These challenges typically include the lowering of the limit of detection, the integration of sample prepn. into the device and hence anal. directly within a sample matrix, finding strategies for long-term in vivo use, etc. Today, functional nanomaterials are synthesized, investigated, and applied in electrochem. biosensors and lab-on-a-chip devices to assist in this endeavor. This review answers many questions around the nanomaterials used, their inherent properties and the chemistries they offer that are of interest to the anal. systems, and their roles in anal. applications in the past 5 years (2013-2018), and it gives a quant. assessment of their pos. effects on the analyses. Furthermore, to facilitate an insightful understanding on how functional nanomaterials can be beneficial and effectively implemented into electrochem. biosensor-based lab-on-a-chip devices, seminal studies discussing important fundamental knowledge regarding device fabrication and nanomaterials are comprehensively included here. The review ultimately gives answers to the ultimate question: "Are they really needed or can bulk materials accomplish the same" Finally, challenges and future directions are also discussed.
- 13Nguyen, H.; Park, J.; Kang, S.; Kim, M. Surface Plasmon Resonance: A Versatile Technique for Biosensor Applications. Sensors 2015, 15, 10481– 10510, DOI: 10.3390/s150510481Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXptlKqurw%253D&md5=98cc17f36c89a34ab7db91932cbcb954Surface plasmon resonance: a versatile technique for biosensor applicationsNguyen, Hoang Hiep; Park, Jeho; Kang, Sebyung; Kim, MoonilSensors (2015), 15 (5), 10481-10510CODEN: SENSC9; ISSN:1424-8220. (MDPI AG)A review. Surface plasmon resonance (SPR) is a label-free detection method which has emerged during the last two decades as a suitable and reliable platform in clin. anal. for biomol. interactions. The technique makes it possible to measure interactions in real-time with high sensitivity and without the need of labels. This review article discusses a wide range of applications in optical-based sensors using either surface plasmon resonance (SPR) or surface plasmon resonance imaging (SPRI). Here we summarize the principles, provide examples, and illustrate the utility of SPR and SPRI through example applications from the biomedical, proteomics, genomics and bioengineering fields. In addn., SPR signal amplification strategies and surface functionalization are covered in the review.
- 14Reimhult, E.; Höök, F. Design of Surface Modifications for Nanoscale Sensor Applications. Sensors 2015, 15, 1635– 1675, DOI: 10.3390/s150101635Google Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2Mros1WisQ%253D%253D&md5=da99f5bcc143b6247a288ac9280852b9Design of surface modifications for nanoscale sensor applicationsReimhult Erik; Hook FredrikSensors (Basel, Switzerland) (2015), 15 (1), 1635-75 ISSN:.Nanoscale biosensors provide the possibility to miniaturize optic, acoustic and electric sensors to the dimensions of biomolecules. This enables approaching single-molecule detection and new sensing modalities that probe molecular conformation. Nanoscale sensors are predominantly surface-based and label-free to exploit inherent advantages of physical phenomena allowing high sensitivity without distortive labeling. There are three main criteria to be optimized in the design of surface-based and label-free biosensors: (i) the biomolecules of interest must bind with high affinity and selectively to the sensitive area; (ii) the biomolecules must be efficiently transported from the bulk solution to the sensor; and (iii) the transducer concept must be sufficiently sensitive to detect low coverage of captured biomolecules within reasonable time scales. The majority of literature on nanoscale biosensors deals with the third criterion while implicitly assuming that solutions developed for macroscale biosensors to the first two, equally important, criteria are applicable also to nanoscale sensors. We focus on providing an introduction to and perspectives on the advanced concepts for surface functionalization of biosensors with nanosized sensor elements that have been developed over the past decades (criterion (iii)). We review in detail how patterning of molecular films designed to control interactions of biomolecules with nanoscale biosensor surfaces creates new possibilities as well as new challenges.
- 15Waggoner, P. S.; Craighead, H. G. Micro- and Nanomechanical Sensors for Environmental, Chemical, and Biological Detection. Lab Chip 2007, 7, 1238– 1255, DOI: 10.1039/b707401hGoogle Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtVOrtL%252FE&md5=9713ef6c5678177a3fe1b897951b1d0eMicro- and nanomechanical sensors for environmental, chemical, and biological detectionWaggoner, Philip S.; Craighead, Harold G.Lab on a Chip (2007), 7 (10), 1238-1255CODEN: LCAHAM; ISSN:1473-0197. (Royal Society of Chemistry)A review. Micro- and nanoelectromech. systems, including cantilevers and other small scale structures, were studied for sensor applications. Accurate sensing of gaseous or aq. environments, chem. vapors, and biomols. were demonstrated using a variety of these devices that undergo static deflections or shifts in resonant frequency upon analyte binding. In particular, biol. detection of viruses, antigens, DNA, and other proteins is of great interest. While the majority of currently used detection schemes are reliant on biomarkers, such as fluorescent labels, time, effort, and chem. activity could be saved by developing an ultrasensitive method of label-free mass detection. Micro- and nanoscale sensors were effectively applied as label-free detectors. In the following, the authors review the technologies and recent developments in the field of micro- and nanoelectromech. sensors with particular emphasis on their application as biol. sensors and recent work towards integrating these sensors in microfluidic systems.
- 16Pitruzzello, G.; Krauss, T. F. Photonic crystal resonances for sensing and imaging. J. Opt. 2018, 20, 073004, DOI: 10.1088/2040-8986/aac75bGoogle Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXkvFant7Y%253D&md5=57ec9f410af4c4dd1b9a53c6ebb14202Photonic crystal resonances for sensing and imagingPitruzzello, Giampaolo; Krauss, Thomas F.Journal of Optics (Bristol, United Kingdom) (2018), 20 (7), 073004/1-073004/23CODEN: JOOPCA; ISSN:2040-8978. (IOP Publishing Ltd.)This review provides an insight into the recent developments of photonic crystal (PhC)-based devices for sensing and imaging, with a particular emphasis on biosensors. We focus on two main classes of devices, namely sensors based on PhC cavities and those on guided mode resonances (GMRs). This distinction is able to capture the richness of possibilities that PhCs are able to offer in this space. We present recent examples highlighting applications where PhCs can offer new capabilities, open up new applications or enable improved performance, with a clear emphasis on the different types of structures and photonic functions. We provide a crit. comparison between cavity-based devices and GMR devices by highlighting strengths and weaknesses. We also compare PhC technologies and their sensing mechanism to surface plasmon resonance, microring resonators and integrated interferometric sensors.
- 17Greenwood, D. β-Lactam Antibiotics—Cephalosporins. In Antibiotic and Chemotherapy, 9th ed.; Finch, R. G., Greenwood, D., Norrby, S. R., Whitely, R. J., Eds.; Saunders, 2010; Chapter 13, pp 170– 199.Google ScholarThere is no corresponding record for this reference.
- 18Qi, X.; Gunawan, P.; Xu, R.; Chang, M. W. Cefalexin-immobilized Multi-walled Carbon Nanotubes Show Strong Antimicrobial and Anti-adhesion Properties. Chem. Eng. Sci. 2012, 84, 552– 556, DOI: 10.1016/j.ces.2012.08.054Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1eiur3E&md5=28e493ae00303f1f415f16e19cb4cc88Cefalexin-immobilized multi-walled carbon nanotubes show strong antimicrobial and anti-adhesion propertiesQi, Xiaobao; Gunawan, Poernomo; Xu, Rong; Chang, Matthew WookChemical Engineering Science (2012), 84 (), 552-556CODEN: CESCAC; ISSN:0009-2509. (Elsevier Ltd.)Multi-walled carbon nanotubes (MWNTs) possess weak antimicrobial property. In this report, we demonstrate that the covalent immobilization of the antibiotic cefalexin via poly(ethylene glycol) as a linking agent improves the antimicrobial and anti-adhesive properties of MWNTs against both Gram-neg. bacteria (Escherichia coli and Pseudomonas aeruginosa) and Gram-pos. bacteria (Staphylococcus aureus and Bacillus subtilis). In particular, the MWNT-cefalexin composite showed 2-fold higher antimicrobial property than pristine MWNTs against S. aureus and B. subtilis. Moreover, the MWNT-cefalexin deposited film effectively inhibited cell adhesion. Given the simple, inexpensive procedures of our synthesis method, the MWNT-cefalexin composite has the potential to be used as an effective and economical antibacterial and anti-adhesion material for environmental and biomedical applications.
- 19Dreesen, L.; Silien, C.; Volcke, C.; Sartenaer, Y.; Thiry, P. A.; Peremans, A.; Grugier, J.; Marchand-Brynaert, J.; Brans, A.; Grubisic, S.; Joris, B. Adsorption Properties of the Penicillin Derivative DTPA on Gold Substrates. ChemPhysChem 2007, 8, 1071– 1076, DOI: 10.1002/cphc.200700087Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXlvVGksrg%253D&md5=69a58dbbd6567420aa36ed86fc230f7eAdsorption properties of the penicillin derivative DTPA on gold substratesDreesen, Laurent; Silien, Christophe; Volcke, Cedric; Sartenaer, Yannick; Thiry, Paul A.; Peremans, Andre; Grugier, Jerome; Marchand-Brynaert, Jacqueline; Brans, Alain; Grubisic, Stana; Joris, BernardChemPhysChem (2007), 8 (7), 1071-1076CODEN: CPCHFT; ISSN:1439-4235. (Wiley-VCH Verlag GmbH & Co. KGaA)Despite the large no. of articles and patents dealing with penicillin and other β-lactam antibiotics, there were no reports about the self-assembly of such substances as monolayers on gold surfaces. The main reason stems from the high reactivity of the β-lactam ring, which hinders the development of mols. possessing this entity together with a metal-anchoring function. Herein, the authors present the synthesis of a novel mol., 6-[(R,S)-5-(1,2-dithiolan-3-yl)pentanoyl-amino]-penicillanic acid (DTPA), which combines the β-lactam ring and a metal-anchoring group. Using spectroscopic tools, the authors demonstrate the chemisorption of this compd. on gold as self-assembled monolayers without any alteration of the penicillin pharmacophore and document its reactivity towards a penicillin-binding protein, BlaR-CTD. The authors' work is a preliminary step towards the development of new biosensors and well-ordered protein arrays, both based on the high affinity of penicillin for penicillin-binding proteins.
- 20Tarrat, N.; Benoit, M.; Giraud, M.; Ponchet, A.; Casanove, M. J. The Gold/Ampicillin Interface at the Atomic Scale. Nanoscale 2015, 7, 14515– 14524, DOI: 10.1039/c5nr03318gGoogle Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1Khs7vO&md5=7993e0105da92e28a43b20ecaf920fbfThe gold/ampicillin interface at the atomic scaleTarrat, N.; Benoit, M.; Giraud, M.; Ponchet, A.; Casanove, M. J.Nanoscale (2015), 7 (34), 14515-14524CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)In the fight against antibiotic resistance, gold nanoparticles (AuNP) with antibiotics grafted on their surfaces have been found to be potent agents. Ampicillin-conjugated AuNPs have been thus reported to overcome highly ampicillin-resistant bacteria. However, the structure at the at. scale of these hybrid systems remains misunderstood. In this paper, the structure of the interface between an ampicillin mol. AMP and three flat gold facets Au(111), Au(110) and Au(100) has been investigated with numerical simulations (dispersion-cor. DFT). Adsorption energies, bond distances and electron densities indicate that the adsorption of AMP on these facets goes through multiple partially covalent bonding. The stability of the AuNP/AMP nanoconjugates is explained by large adsorption energies and their potential antibacterial activity is discussed on the basis of the constrained spatial orientation of the grafted antibiotic.
- 21Padayatti, P. S.; Helfand, M. S.; Totir, M. A.; Carey, M. P.; Carey, P. R.; Bonomo, R. A.; van den Akker, F. High Resolution Crystal Structures of the trans-Enamine Intermediates Formed by Sulbactam and Clavulanic Acid and E166A SHV-1 β-Lactamase. J. Biol. Chem. 2005, 280, 34900– 34907, DOI: 10.1074/jbc.m505333200Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtVyks7%252FE&md5=248b3dd549e2b483428f7b29c13d967aHigh Resolution Crystal Structures of the trans-Enamine Intermediates Formed by Sulbactam and Clavulanic Acid and E166A SHV-1 β-LactamasePadayatti, Pius S.; Helfand, Marion S.; Totir, Monica A.; Carey, Marianne P.; Carey, Paul R.; Bonomo, Robert A.; van den Akker, FoccoJournal of Biological Chemistry (2005), 280 (41), 34900-34907CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Antibiotic resistance mediated by constantly evolving β-lactamases is a serious threat to human health. The mechanism of inhibition of these enzymes by therapeutic β-lactamase inhibitors is probed using a novel approach involving Raman microscopy and x-ray crystallog. We have presented here the high resoln. crystal structures of the β-lactamase inhibitors sulbactam and clavulanic acid bound to the deacylation-deficient E166A variant of SHV-1 β-lactamase. Our previous Raman measurements have identified the trans-enamine species for both inhibitors and were used to guide the soaking time and concn. to achieve full occupancy of the active sites. The two inhibitor-bound x-ray structures revealed a linear trans-enamine intermediate covalently attached to the active site Ser-70 residue. This intermediate was thought to play a key role in the transient inhibition of class A β-lactamases. Both the Raman and x-ray data indicated that the clavulanic acid intermediate is decarboxylated. When compared with our previously detd. tazobactam-bound inhibitor structure, our new inhibitor-bound structures revealed an increased disorder in the tail region of the inhibitors as well as in the enamine skeleton. The x-ray crystallog. observations correlated with the broadening of the O-C=C-N (enamine) sym. stretch Raman band near 1595 cm-1. Band broadening in the sulbactam and clavulanic acid intermediates reflected a heterogeneous conformational population that results from variations of torsional angles in the O-(C=O)-C=C=NH-C skeleton. These observations led us to conclude that the conformational stability of the trans-enamine form is crit. for their transient inhibitory efficacy.
- 22Prime, K. L.; Whitesides, G. M. Adsorption of Proteins onto Surfaces Containing End-attached Oligo(ethylene oxide): A Model System Using Self-assembled Monolayers. J. Am. Chem. Soc. 1993, 115, 10714– 10721, DOI: 10.1021/ja00076a032Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXmsVCrtbk%253D&md5=2bc4272cf29fc4109818160bea5f7f30Adsorption of proteins onto surfaces containing end-attached oligo(ethylene oxide): a model system using self-assembled monolayersPrime, Kevin L.; Whitesides, George M.Journal of the American Chemical Society (1993), 115 (23), 10714-21CODEN: JACSAT; ISSN:0002-7863.This paper reports a study of the adsorption of four proteins-fibrinogen, lysozyme, pyruvate kinase, and RNAse A-to self-assembled monolayers (SAMs) on gold. The SAMs examd. were derived from thiols of the structure HS(CH2)10R, where R was CH3, CH2OH, and oligo(ethylene oxide). Monolayers that contained a sufficiently large mole fraction of alkanethiolate groups terminated in oligo(ethylene oxide) chains resisted the kinetically irreversible, nonspecific adsorption of all four proteins. Longer chains of oligo(ethylene oxide) were resistant at lower mole fractions in the monolayer. Resistance to the adsorption of proteins increased with the length of the oligo(ethylene oxide) chain: the smallest mole fraction of chains that prevented adsorption was proportional to n-0.4, where n represents the no. of ethylene oxide units per chain. Termination of the oligo(ethylene oxide) chains with a methoxy group instead of a hydroxyl group had little or no effect on the amt. of protein adsorbed. The amt. of pyruvate kinase that adsorbed to mixed SAMs contg. hexa(ethylene oxide)-terminated chains depended upon the temp. When the mole fraction of oligo(ethylene oxide) groups in the monolayer was below the level needed to prevent adsorption, more pyruvate kinase adsorbed to the monolayer at 37°C than at 25°C. No difference was obsd. between adsorption at 25 and 4°C.
- 23Banerjee, I.; Pangule, R. C.; Kane, R. S. Antifouling Coatings: Recent Developments in the Design of Surfaces that Prevent Fouling by Proteins, Bacteria, and Marine Organisms. Adv. Mater. 2011, 23, 690– 718, DOI: 10.1002/adma.201001215Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVOmtLw%253D&md5=60430143bc3f7595c0f46731f168d224Antifouling Coatings: Recent Developments in the Design of Surfaces That Prevent Fouling by Proteins, Bacteria, and Marine OrganismsBanerjee, Indrani; Pangule, Ravindra C.; Kane, Ravi S.Advanced Materials (Weinheim, Germany) (2011), 23 (6), 690-718CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The major strategies for designing surfaces that prevent fouling due to proteins, bacteria, and marine organisms are reviewed. Biofouling is of great concern in numerous applications. The two major approaches to combat surface fouling are based on either preventing biofoulants from attaching or degrading them. While protein-resistant coatings may also resist bacterial attachment and subsequent biofilm formation, in order to overcome the fouling-mediated risk of bacterial infection it is highly desirable to design coatings that are bactericidal. Traditional techniques involve the design of coatings that release biocidal agents. However, the emergence of antibiotic- and silver-resistant pathogenic strains has necessitated the development of alternative strategies. Therefore, other techniques are being investigated. With regard to marine antifouling coatings, restrictions on the use of biocide-releasing coatings have made the generation of nontoxic antifouling surfaces more important. While considerable progress has been made in the design of antifouling coatings, ongoing research in this area should result in the development of even better antifouling materials in the future.
- 24Mehne, J.; Markovic, G.; Pröll, F.; Schweizer, N.; Zorn, S.; Schreiber, F.; Gauglitz, G. Characterisation of morphology of self-assembled PEG monolayers: a comparison of mixed and pure coatings optimised for biosensor applications. Anal. Bioanal. Chem. 2008, 391, 1783– 1791, DOI: 10.1007/s00216-008-2066-0Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXnsFakur8%253D&md5=bcce546491c8895c9cec7a194875e905Characterisation of morphology of self-assembled PEG monolayers: a comparison of mixed and pure coatings optimised for biosensor applicationsMehne, Jochen; Markovic, Goran; Proell, Florian; Schweizer, Nina; Zorn, Stefan; Schreiber, Frank; Gauglitz, GuenterAnalytical and Bioanalytical Chemistry (2008), 391 (5), 1783-1791CODEN: ABCNBP; ISSN:1618-2642. (Springer)For detection of low concns. of analytes in complex biol. matrixes using optical biosensors, a high surface loading with capture mols. and a low nonspecific binding of nonrelevant matrix mols. are essential. To tailor biosensor surfaces in such a manner, poly(ethylene glycols) (PEG) in varying lengths were immobilized covalently onto glass-type surfaces in different mixing ratios and concns., and were subsequently modified with three different kinds of receptors. The nonspecific binding of a model protein (ovalbumin, OVA) and the max. loading of the resp. analytes to these prepd. surfaces were monitored using label-free and time-resolved reflectometric interference spectroscopy (RIfS). The three different analytes used varied in size: 150 kDa for the anti-atrazine antibody, 60 kDa for streptavidin and 5 kDa for the 15-bp oligonucleotide. The authors investigated if the mixing of PEG in different lengths could increase the surface loadings of analyte mimicking a three-dimensional matrix as was found using dextrans as sensor coatings. In addn., the effect on the surface loading was investigated with regard to the size of the analyte mol. using such mixed PEGs on the sensor surface. For further characterization of the surface coatings, polarization modulation IR reflection absorption spectroscopy, at. force microscopy, and ellipsometry were applied.
- 25Unsworth, L. D.; Sheardown, H.; Brash, J. L. Polyethylene Oxide Surfaces of Variable Chain Density by Chemisorption of PEO-thiol on Gold: Adsorption of Proteins from Plasma Studied by Radiolabelling and Immunoblotting. Biomaterials 2005, 26, 5927– 5933, DOI: 10.1016/j.biomaterials.2005.03.010Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXlt1WgsLc%253D&md5=a6ef6d631ce2edae598789b2bc8f172aPolyethylene oxide surfaces of variable chain density by chemisorption of PEO-thiol on gold: Adsorption of proteins from plasma studied by radiolabelling and immunoblottingUnsworth, Larry D.; Sheardown, Heather; Brash, John L.Biomaterials (2005), 26 (30), 5927-5933CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)The mechanisms involved in the inhibition of protein adsorption by polyethylene oxide (PEO) are not completely understood, but it is believed that PEO chain length, chain d. and chain conformation all play a role. In this work, surfaces formed by chemisorption of PEO-thiol to gold were investigated: the effects of PEO chain d., chain length (600, 750, 2000 and 5000 MW) and end-group (-OH, -OCH3) on protein adsorption from plasma are reported. Similar to previous single protein adsorption studies (L.D. Unsworth et al., Langmuir 2005;21:1036-41) it was found that, of the different surfaces investigated, PEO layers formed from solns. near the cloud point adsorbed the lowest amt. of fibrinogen from plasma. Layers of hydroxyl-terminated PEO of MW 600 formed under these low soly. conditions showed almost complete suppression (vs. controls) of the Vroman effect, with 20±1 ng/cm2 adsorbed fibrinogen at the Vroman peak and 6.7±0.6 ng/cm2 at higher plasma concn. By comparison, Vroman peak adsorption was 70±20 and 50±3 ng/cm2, resp., for 750-OCH3 and 2000-OCH3 layers formed under low soly. conditions; adsorption on these surfaces at higher plasma concn. was 16±9 and 12±3 ng/cm2. Thus in addn. to the effect of soln. conditions noted previously, the results of this study also suggest a chain end group effect which inhibits fibrinogen adsorption to, and/or facilitates displacement from, hydroxyl terminated PEO layers. Fibrinogen adsorption from plasma was not significantly different for surfaces prepd. with PEO of mol. wt. 750 and 2000 when the chain d. was the same (∼0.5 chains/nm2) supporting the conclusion that chain d. may be the key property for suppression of protein adsorption. The proteins eluted from the surfaces after contact with plasma were investigated by SDS-PAGE and immunoblotting. A no. of proteins were detected on the various surfaces including fibrinogen, albumin, C3 and apolipoprotein A-I. The blot responses were zero or weak for all four proteins of the contact system; some complement activation was obsd. on all of the surfaces studied.
- 26Hinterwirth, H.; Kappel, S.; Waitz, T.; Prohaska, T.; Lindner, W.; Lämmerhofer, M. Quantifying Thiol Ligand Density of Self-Assembled Monolayers on Gold Nanoparticles by Inductively Coupled Plasma-Mass Spectrometry. ACS Nano 2013, 7, 1129– 1136, DOI: 10.1021/nn306024aGoogle Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFWrsbw%253D&md5=7bbb8884425a162715668ef87418ab27Quantifying Thiol Ligand Density of Self-Assembled Monolayers on Gold Nanoparticles by Inductively Coupled Plasma-Mass SpectrometryHinterwirth, Helmut; Kappel, Stefanie; Waitz, Thomas; Prohaska, Thomas; Lindner, Wolfgang; Laemmerhofer, MichaelACS Nano (2013), 7 (2), 1129-1136CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)Gold nanoparticles (GNPs) are often used as colloidal carriers in numerous applications owing to their low-cost and size-controlled prepn. as well as their straightforward surface functionalization with thiol contg. mols. forming self-assembling monolayers (SAM). The quantification of the ligand d. of such modified GNPs is tech. challenging, yet of utmost importance for quality control in many applications. In this contribution, a new method for the detn. of the surface coverage of GNPs with thiol contg. ligands is proposed. It makes use of the measurement of the gold-to-sulfur (Au/S) ratio by inductively coupled plasma mass spectrometry (ICP-MS) and its dependence on the nanoparticle diam. The simultaneous ICP-MS measurement of gold and sulfur was carefully validated and found to be a robust method with a relative std. uncertainty of lower than 10%. A major advantage of this method is the independence from sample prepn.; for example, sample loss during the washing steps is not affecting the results. To demonstrate the utility of the straightforward method, GNPs of different diams. were synthesized and derivatized on the surface with bifunctional (lipophilic) ω-mercapto-alkanoic acids and (hydrophilic) mercapto-poly(ethylene glycol) (PEG)n-carboxylic acids by self-assembling monolayer (SAM) formation. A size-independent but ligand-chain length-dependent ligand d. was found. The surface coverage increases from 4.3 to 6.3 mols. nm-2 with a decrease of ligand chain length from 3.52 to 0.68 nm. Furthermore, no significant difference between the surface coverage of hydrophilic and lipophilic ligands with approx. the same ligand length was found, indicating that steric hindrance is of more importance than, for example, intermol. strand interactions of Van der Waals forces as claimed in other studies.
- 27Chang, E. P.; Roncal-Herrero, T.; Morgan, T.; Dunn, K. E.; Rao, A.; Kunitake, J. A. M. R.; Lui, S.; Bilton, M.; Estroff, L. A.; Kröger, R.; Johnson, S.; Cölfen, H.; Evans, J. S. Synergistic Biomineralization Phenomena Created by a Combinatorial Nacre Protein Model System. Biochemistry 2016, 55, 2401– 2410, DOI: 10.1021/acs.biochem.6b00163Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XlvVCjs7c%253D&md5=7815c1adf9502a183e1b2706101f9037Synergistic Biomineralization Phenomena Created by a Combinatorial Nacre Protein Model SystemChang, Eric P.; Roncal-Herrero, Teresa; Morgan, Tamara; Dunn, Katherine E.; Rao, Ashit; Kunitake, Jennie A. M. R.; Lui, Susan; Bilton, Matthew; Estroff, Lara A.; Kroger, Roland; Johnson, Steven; Colfen, Helmut; Evans, John SpencerBiochemistry (2016), 55 (16), 2401-2410CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)In the nacre or aragonite layer of the mollusk shell, proteomes that regulate both the early stages of nucleation and nano-to-mesoscale assembly of nacre tablets from mineral nanoparticle precursors exist. Several approaches have been developed to understand protein-assocd. mechanisms of nacre formation, yet we still lack insight into how protein ensembles or proteomes manage nucleation and crystal growth. To provide addnl. insights, we have created a proportionally defined combinatorial model consisting of two nacre-assocd. proteins, C-RING AP7 (shell nacre, Haliotis rufescens) and pseudo-EF hand PFMG1 (oyster pearl nacre, Pinctada fucata), whose individual in vitro mineralization functionalities are well-documented and distinct from one another. Using SEM, flow cell scanning transmission electron microscopy, at. force microscopy, Ca(II) potentiometric titrns., and quartz crystal microbalance with dissipation monitoring quant. analyses, we find that both nacre proteins are functionally active within the same mineralization environments and, at 1:1 molar ratios, synergistically create calcium carbonate mesoscale structures with ordered intracryst. nanoporosities, extensively prolong nucleation times, and introduce an addnl. nucleation event. Further, these two proteins jointly create nanoscale protein aggregates or phases that under mineralization conditions further assemble into protein-mineral polymer-induced liq. precursor-like phases with enhanced ACC stabilization capabilities, and there is evidence of intermol. interactions between AP7 and PFMG1 under these conditions. Thus, a combinatorial model system consisting of more than one defined biomineralization protein dramatically changes the outcome of the in vitro biomineralization process.
- 28Davenport, M.; Mach, K. E.; Shortliffe, L. M. D.; Banaei, N.; Wang, T.-H.; Liao, J. C. New and developing diagnostic technologies for urinary tract infections. Nat. Rev. Urol. 2017, 14, 296– 310, DOI: 10.1038/nrurol.2017.20Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1czhslGntg%253D%253D&md5=ca102f0137ea34d7bb8e8a943ff1039bNew and developing diagnostic technologies for urinary tract infectionsDavenport Michael; Mach Kathleen E; Shortliffe Linda M Dairiki; Liao Joseph C; Banaei Niaz; Wang Tza-Huei; Liao Joseph CNature reviews. Urology (2017), 14 (5), 296-310 ISSN:.Timely and accurate identification and determination of the antimicrobial susceptibility of uropathogens is central to the management of UTIs. Urine dipsticks are fast and amenable to point-of-care testing, but do not have adequate diagnostic accuracy or provide microbiological diagnosis. Urine culture with antimicrobial susceptibility testing takes 2-3 days and requires a clinical laboratory. The common use of empirical antibiotics has contributed to the rise of multidrug-resistant organisms, reducing treatment options and increasing costs. In addition to improved antimicrobial stewardship and the development of new antimicrobials, novel diagnostics are needed for timely microbial identification and determination of antimicrobial susceptibilities. New diagnostic platforms, including nucleic acid tests and mass spectrometry, have been approved for clinical use and have improved the speed and accuracy of pathogen identification from primary cultures. Optimization for direct urine testing would reduce the time to diagnosis, yet these technologies do not provide comprehensive information on antimicrobial susceptibility. Emerging technologies including biosensors, microfluidics, and other integrated platforms could improve UTI diagnosis via direct pathogen detection from urine samples, rapid antimicrobial susceptibility testing, and point-of-care testing. Successful development and implementation of these technologies has the potential to usher in an era of precision medicine to improve patient care and public health.
- 29Geertsma, E. R.; Poolman, B. High-throughput cloning and expression in recalcitrant bacteria. Nat. Methods 2007, 4, 705– 707, DOI: 10.1038/nmeth1073Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXps12gsLc%253D&md5=8dda823cd44b8c30c973c10f4117f3a0High-throughput cloning and expression in recalcitrant bacteriaGeertsma, Eric R.; Poolman, BertNature Methods (2007), 4 (9), 705-707CODEN: NMAEA3; ISSN:1548-7091. (Nature Publishing Group)We developed a generic method for high-throughput cloning in bacteria that are less amenable to conventional DNA manipulations. The method involves ligation-independent cloning in an intermediary Escherichia coli vector, which is rapidly converted via vector-backbone exchange (VBEx) into an organism-specific plasmid ready for high-efficiency transformation. We demonstrated VBEx proof of principle for Lactococcus lactis, but the method can be adapted to all organisms for which plasmids are available.
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Abstract
Scheme 1
Scheme 1. Design of the Surface-Bound AntibioticaaSAM formation and attachment of cephalexin via a maleimide tether. For Au surfaces, X = SH; for SiO2 surfaces, X = Si(OEt)3. Inset: Structure of cephalexin (1) and cephalexin-R-maleimide (2), where R = CH2OCH2C(O)NHCH2PEG4CH2NHC(O)(CH2)5.
Figure 1
Figure 1. Structure of cephalexin-PEG-maleimide (2). PM-IRRAS spectra of the cephalexin-PEG surface before (red) and after (blue) exposure to β-lactamases.
Figure 2
Figure 2. QCM-D experiment monitoring cephalexin-PEG (2) binding to the thiolated surfaces of SiO2 and Au sensors. The introduction of each solution is indicated by labeled arrows and dashed lines.
Figure 3
Figure 3. (a) Use of PBP as a probe for QCM-D studies. (b) QCM-D experiment of surface-bound cephalexin-PEG (2) on Au: (1) PBP only; (2) PBP preincubated with cephalexin; (3) surface antibiotics pre-treated with NaOH, a gap in the data indicates a skipped buffer step. The introduction of each solution is shown by labeled arrows and dashed lines. The number of PBPs bound after the final wash is shown for each sensor. Data reported as mean value ± standard deviation.
Figure 4
Figure 4. QCM-D experiment of surface-bound cephalexin-PEG (2) on Au: (1) PBPs only and (2) β-lactamases followed by PBPs. The introduction of each solution is shown by labeled arrows and dashed lines. The number of PBPs bound after the final wash is shown for each sensor. Data reported as mean value ± standard deviation.
Figure 5
Figure 5. PM-IRRAS and QCM-D studies in urine. (a) PM-IRRAS test: before and after exposure to urine spiked with β-lactamases. (b) PM-IRRAS control: before and after exposure to urine only. (c) QCM-D experiment of surface-bound cephalexin-PEG (2) on Au: (1) urine only and (2) urine spiked with β-lactamases. The introduction of each solution is shown by labeled arrows and dashed lines. The number of PBPs bound after the final wash is shown for each sensor. Data reported as mean value ± standard deviation.
References
ARTICLE SECTIONSThis article references 29 other publications.
- 1Sultan, I.; Rahman, S.; Jan, A. T.; Siddiqui, M. T.; Mondal, A. H.; Haq, Q. M. R. Antibiotics, Resistome and Resistance Mechanisms: A Bacterial Perspective. Front. Microbiol. 2018, 9, 2066, DOI: 10.3389/fmicb.2018.02066Google Scholar1https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3czntVCiuw%253D%253D&md5=3eaa839bd598f33b4b1262b56c16173eAntibiotics, Resistome and Resistance Mechanisms: A Bacterial PerspectiveSultan Insha; Siddiqui Mohammad Tahir; Mondal Aftab Hossain; Haq Qazi Mohd Rizwanul; Rahman Safikur; Jan Arif TasleemFrontiers in microbiology (2018), 9 (), 2066 ISSN:1664-302X.History of mankind is regarded as struggle against infectious diseases. Rather than observing the withering away of bacterial diseases, antibiotic resistance has emerged as a serious global health concern. Medium of antibiotic resistance in bacteria varies greatly and comprises of target protection, target substitution, antibiotic detoxification and block of intracellular antibiotic accumulation. Further aggravation to prevailing situation arose on observing bacteria gradually becoming resistant to different classes of antibiotics through acquisition of resistance genes from same and different genera of bacteria. Attributing bacteria with feature of better adaptability, dispersal of antibiotic resistance genes to minimize effects of antibiotics by various means including horizontal gene transfer (conjugation, transformation, and transduction), Mobile genetic elements (plasmids, transposons, insertion sequences, integrons, and integrative-conjugative elements) and bacterial toxin-antitoxin system led to speedy bloom of antibiotic resistance amongst bacteria. Proficiency of bacteria to obtain resistance genes generated an unpleasant situation; a grave, but a lot unacknowledged, feature of resistance gene transfer.
- 2Davies, J.; Davies, D. Origins and Evolution of Antibiotic Resistance. Microbiol. Mol. Biol. Rev. 2010, 74, 417– 433, DOI: 10.1128/mmbr.00016-10Google Scholar2https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVSqurnO&md5=64214f42f2ae91c1ba94dbe765b7cd0cOrigins and evolution of antibiotic resistanceDavies, Julian; Davies, DorothyMicrobiology and Molecular Biology Reviews (2010), 74 (3), 417-433CODEN: MMBRF7; ISSN:1092-2172. (American Society for Microbiology)A review. Antibiotics have always been considered one of the wonder discoveries of the 20th century. This is true, but the real wonder is the rise of antibiotic resistance in hospitals, communities, and the environment concomitant with their use. The extraordinary genetic capacities of microbes have benefitted from man's overuse of antibiotics to exploit every source of resistance genes and every means of horizontal gene transmission to develop multiple mechanisms of resistance for each and every antibiotic introduced into practice clin., agriculturally, or otherwise. This review presents the salient aspects of antibiotic resistance development over the past half-century, with the oft-restated conclusion that it is time to act. To achieve complete restitution of therapeutic applications of antibiotics, there is a need for more information on the role of environmental microbiomes in the rise of antibiotic resistance. In particular, creative approaches to the discovery of novel antibiotics and their expedited and controlled introduction to therapy are obligatory.
- 3Klein, E. Y.; Van Boeckel, T. P.; Martinez, E. M.; Pant, S.; Gandra, S.; Levin, S. A.; Goossens, H.; Laxminarayan, R. Global Increase and Geographic Convergence in Antibiotic Consumption Between 2000 and 2015. Proc. Natl. Acad. Sci. U.S.A. 2018, 115, E3463– E3470, DOI: 10.1073/pnas.1817182115Google Scholar3https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXht1Gqt7jM&md5=7888300662d6de00d91a7b5c26844657Global increase and geographic convergence in antibiotic consumption between 2000 and 2015Klein, Eili Y.; Boeckel, Thomas P. Van; Martinez, Elena M.; Pant, Suraj; Gandra, Sumanth; Levin, Simon A.; Goossens, Herman; Laxminarayan, RamananProceedings of the National Academy of Sciences of the United States of America (2018), 115 (15), E3463-E3470CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Tracking antibiotic consumption patterns over time and across countries could inform policies to optimize antibiotic prescribing and minimize antibiotic resistance, such as setting and enforcing per capita consumption targets or aiding investments in alternatives to antibiotics. In this study, we analyzed the trends and drivers of antibiotic consumption from 2000 to 2015 in 76 countries and projected total global antibiotic consumption through 2030. Between 2000 and 2015, antibiotic consumption, expressed in defined daily doses (DDD), increased 65% (21.1-34.8 billion DDDs), and the antibiotic consumption rate increased 39% (11.3-15.7 DDDs per 1,000 inhabitants per day). The increase was driven by low- and middle-income countries (LMICs), where rising consumption was correlated with gross domestic product per capita (GDPPC) growth (P = 0.004). In high-income countries (HICs), although overall consumption increased modestly, DDDs per 1,000 inhabitants per day fell 4%, and there was no correlation with GDPPC. Of particular concern was the rapid increase in the use of last-resort compds., both in HICs and LMICs, such as glycylcyclines, oxazolidinones, carbapenems, and polymyxins. Projections of global antibiotic consumption in 2030, assuming no policy changes, were up to 200% higher than the 42 billion DDDs estd. in 2015. Although antibiotic consumption rates in most LMICs remain lower than in HICs despite higher bacterial disease burden, consumption in LMICs is rapidly converging to rates similar to HICs. Reducing global consumption is crit. for reducing the threat of antibiotic resistance, but redn. efforts must balance access limitations in LMICs and take account of local and global resistance patterns.
- 4Syal, K.; Mo, M.; Yu, H.; Iriya, R.; Jing, W.; Guodong, S.; Wang, S.; Grys, T. E.; Haydel, S. E.; Tao, N. Current and Emerging Techniques for Antibiotic Susceptibility Tests. Theranostics 2017, 7, 1795– 1805, DOI: 10.7150/thno.19217Google Scholar4https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvFyju7%252FL&md5=65c2f5678447e904d99d0406267f48aeCurrent and emerging techniques for antibiotic susceptibility testsSyal, Karan; Mo, Manni; Yu, Hui; Iriya, Rafael; Jing, Wenwen; Guodong, Sui; Wang, Shaopeng; Grys, Thomas E.; Haydel, Shelley E.; Tao, NongjianTheranostics (2017), 7 (7), 1795-1805CODEN: THERDS; ISSN:1838-7640. (Ivyspring International Publisher)Infectious diseases caused by bacterial pathogens are a worldwide burden. Serious bacterial infection-related complications, such as sepsis, affect over a million people every year with mortality rates ranging from 30% to 50%. Crucial clin. microbiol. lab. responsibilities assocd. with patient management and treatment include isolating and identifying the causative bacterium and performing antibiotic susceptibility tests (ASTs), which are labor-intensive, complex, imprecise, and slow (taking days, depending on the growth rate of the pathogen). Considering the life-threatening condition of a septic patient and the increasing prevalence of antibiotic-resistant bacteria in hospitals, rapid and automated diagnostic tools are needed. This review summarizes the existing com. AST methods and discusses some of the promising emerging AST tools that will empower humans to win the evolutionary war between microbial genes and human wits.
- 5Kresse, H.; Belsey, M. J.; Rovini, H. The Antibacterial Drugs Market. Nat. Rev. Drug Discovery 2007, 6, 19– 20, DOI: 10.1038/nrd2226Google Scholar5https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtlGktbfJ&md5=4461c36146026ffa85b1db0d3ea51a6fThe antibacterial drugs marketKresse, Hedwig; Belsey, Mark J.; Rovini, HolgerNature Reviews Drug Discovery (2007), 6 (1), 19-20CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)There is no expanded citation for this reference.
- 6O’Callaghan, C. H.; Morris, A.; Kirby, S. M.; Shingler, A. H. Novel Method for Detection of β-Lactamases by Using a Chromogenic Cephalosporin Substrate. Antimicrob. Agents Chemother. 1972, 1, 283– 288, DOI: 10.1128/aac.1.4.283Google Scholar6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaE2c7ns1agsg%253D%253D&md5=dc646a87f692cf4413e81d22218da743Novel method for detection of beta-lactamases by using a chromogenic cephalosporin substrateO'Callaghan C H; Morris A; Kirby S M; Shingler A HAntimicrobial agents and chemotherapy (1972), 1 (4), 283-8 ISSN:0066-4804.A new cephalosporin with a highly reactive beta-lactam ring was found to give an immediate color change in the presence of beta-lactamases from many bacteria, including staphylococci, Bacillus species, Enterobacteriaceae, and Pseudomonas. The reaction is confined to organisms producing beta-lactamases, but it is sufficiently sensitive to indicate the presence of this enzyme is small amounts in strains previously considered not to produce it. The compound has an unusual ultraviolet spectrum, and the color change can be followed quantitatively by measuring changes in absorption which occur in the 380- to 500-nm region, where cephalosporins normally have no absorption. The development of color is thought to be a consequence of the beta-lactam ring being unusually highly conjugated with the 3-substituent. Although in the bacteria only beta-lactamases produce this color change, it was found that serum and tissues from experimental animals also rapidly produced the colored breakdown product, which was then excreted in the urine. The mechanism of the mammalian breakdown was considered to be different from that found in bacteria.
- 7deBoer, T. R.; Tarlton, N. J.; Yamaji, R.; Adams-Sapper, S.; Wu, T. Z.; Maity, S.; Vesgesna, G. K.; Sadlowski, C. M.; DePaola, P.; Riley, L. W.; Murthy, N. An Enzyme-Mediated Amplification Strategy Enables Detection of β-Lactamase Activity Directly in Unprocessed Clinical Samples for Phenotypic Detection of β-Lactam Resistance. ChemBioChem 2018, 19, 2173– 2177, DOI: 10.1002/cbic.201800443Google Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslyrtLjJ&md5=ccde5b311030bd1f1ced7ab4b2cecb90An Enzyme-Mediated Amplification Strategy Enables Detection of β-Lactamase Activity Directly in Unprocessed Clinical Samples for Phenotypic Detection of β-Lactam ResistancedeBoer, Tara R.; Tarlton, Nicole J.; Yamaji, Reina; Adams-Sapper, Sheila; Wu, Tiffany Z.; Maity, Santanu; Vesgesna, Giri K.; Sadlowski, Corinne M.; DePaola, Peter, IV; Riley, Lee W.; Murthy, NirenChemBioChem (2018), 19 (20), 2173-2177CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)Biochem. assays that can identify β-lactamase activity directly from patient samples have the potential to significantly improve the treatment of bacterial infections. However, current β-lactamase probes do not have the sensitivity needed to measure β-lactam resistance directly from patient samples. Here, we report the development of an instrument-free signal amplification technol., DETECT, that connects the activity of two enzymes in series to effectively amplify the activity of β-lactamase 40 000-fold, compared to the std. β-lactamase probe nitrocefin.
- 8Gallah, S.; Decre, D.; Genel, N.; Arlet, G. The -Lacta Test for Direct Detection of Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae in Urine. J. Clin. Microbiol. 2014, 52, 3792– 3794, DOI: 10.1128/jcm.01629-14Google Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cbnsVeltw%253D%253D&md5=8190438087e996cd2d3fea0a990f5dffThe β-Lacta test for direct detection of extended-spectrum-β-lactamase-producing Enterobacteriaceae in urineGallah Salah; Decre Dominique; Genel Nathalie; Arlet GuillaumeJournal of clinical microbiology (2014), 52 (10), 3792-4 ISSN:.With the β-Lacta test, production of extended-spectrum β-lactamases (ESBLs) was assayed in 200 urine samples showing Gram-negative bacilli during direct microscopic examination. While 168 samples tested negative, all samples yielding ESBL-producing Enterobacteriaceae after culture gave positive (n = 30) or uninterpretable (n = 2) results. The sensitivity and specificity of ESBL detection were 94% and 100%, respectively.
- 9Yao, H.; So, M.-k.; Rao, J. A Bioluminogenic Substrate for In Vivo Imaging of β-Lactamase Activity. Angew. Chem., Int. Ed. 2007, 46, 7031– 7034, DOI: 10.1002/anie.200701931Google Scholar9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFSqtL%252FO&md5=90e2abf229bbd429e375d501bb8b0c2dA bioluminogenic substrate for in vivo imaging of β-lactamase activityYao, Hequan; So, Min-Kyung; Rao, JianghongAngewandte Chemie, International Edition (2007), 46 (37), 7031-7034CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A caged β-lactam-D-luciferin (Bluco) conjugate can image β-lactamase activity in vivo through a two-step enzymic process. This novel bioluminogenic probe should facilitate the detection of β-lactamase and widen its applications as a reporter.
- 10Zlokarnik, G.; Negulescu, P. A.; Knapp, T. E.; Mere, L.; Burres, N.; Feng, L.; Whitney, M.; Roemer, K.; Tsien, R. Y. Quantitation of Transcription and Clonal Selection of Single Living Cells with β-Lactamase as Reporter. Science 1998, 279, 84– 88, DOI: 10.1126/science.279.5347.84Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXjtVSjsg%253D%253D&md5=25d3beee86614403847e2ec7b26aed18Quantitation of transcription and clonal selection of single living cells with β-lactamase as reporterZlokarnik, Gregor; Negulescu, Paul A.; Knapp, Thomas E.; Mere, Lora; Burres, Neal; Feng, Luxin; Whitney, Michael; Roemer, Klaus; Tsien, Roger Y.Science (Washington, D. C.) (1998), 279 (5347), 84-88CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Gene expression was visualized in single living mammalian cells with β-lactamase as a reporter that hydrolyzes a substrate loaded intracellularly as a membrane-permeant ester. Each enzyme mol. changed the fluorescence of many substrate mols. from green to blue by disrupting resonance energy transfer. This wavelength shift was detectable by eye or color film in individual cells contg. less than 100 β-lactamase mols. The robust change in emission ratio reveals quant. heterogeneity in real-time gene expression, enables clonal selection by flow cytometry, and forms a basis for high-throughput screening of pharmaceutical candidate drugs in living mammalian cells.
- 11Gao, W.; Xing, B.; Tsien, R. Y.; Rao, J. Novel Fluorogenic Substrates for Imaging β-Lactamase Gene Expression. J. Am. Chem. Soc. 2003, 125, 11146– 11147, DOI: 10.1021/ja036126oGoogle Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXmsVelsrk%253D&md5=3ff7d10e2798d1adb0174414da8cb98dNovel Fluorogenic Substrates for Imaging β-Lactamase Gene ExpressionGao, Wenzhong; Xing, Bengang; Tsien, Roger Y.; Rao, JianghongJournal of the American Chemical Society (2003), 125 (37), 11146-11147CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)A new class of small nonfluorescent fluorogenic substrates, based on release of a phenolic dye from a vinylogous cephalosporin, becomes brightly fluorescent after β-lactamase hydrolysis with up to 153-fold enhancement in the fluorescence intensity. Less than 500 fM of β-lactamase in cell lysates can be readily detected, and β-lactamase expression in living cells can be imaged with a red fluorescence deriv. These new fluorogenic substrates should find uses in clin. diagnostics and facilitate the applications of β-lactamase as a biosensor.
- 12Wongkaew, N.; Simsek, M.; Griesche, C.; Baeumner, A. J. Functional Nanomaterials and Nanostructures Enhancing Electrochemical Biosensors and Lab-on-a-Chip Performances: Recent Progress, Applications, and Future Perspective. Chem. Rev. 2019, 119, 120– 194, DOI: 10.1021/acs.chemrev.8b00172Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslKis7nO&md5=a799268cbf763f6e9ebef46c5b6db2c7Functional Nanomaterials and Nanostructures Enhancing Electrochemical Biosensors and Lab-on-a-Chip Performances: Recent Progress, Applications, and Future PerspectiveWongkaew, Nongnoot; Simsek, Marcel; Griesche, Christian; Baeumner, Antje J.Chemical Reviews (Washington, DC, United States) (2019), 119 (1), 120-194CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. Electrochem. biosensors and assocd. lab-on-a-chip devices are the anal. system of choice when rapid and on-site results are needed in medical diagnostics and food safety, for environmental protection, process control, wastewater treatment, and life sciences discovery research among many others. A premier example is the glucose sensor used by diabetic patients. Current research focuses on developing sensors for specific analytes in these application fields and addresses challenges that need to be solved before viable com. products can be designed. These challenges typically include the lowering of the limit of detection, the integration of sample prepn. into the device and hence anal. directly within a sample matrix, finding strategies for long-term in vivo use, etc. Today, functional nanomaterials are synthesized, investigated, and applied in electrochem. biosensors and lab-on-a-chip devices to assist in this endeavor. This review answers many questions around the nanomaterials used, their inherent properties and the chemistries they offer that are of interest to the anal. systems, and their roles in anal. applications in the past 5 years (2013-2018), and it gives a quant. assessment of their pos. effects on the analyses. Furthermore, to facilitate an insightful understanding on how functional nanomaterials can be beneficial and effectively implemented into electrochem. biosensor-based lab-on-a-chip devices, seminal studies discussing important fundamental knowledge regarding device fabrication and nanomaterials are comprehensively included here. The review ultimately gives answers to the ultimate question: "Are they really needed or can bulk materials accomplish the same" Finally, challenges and future directions are also discussed.
- 13Nguyen, H.; Park, J.; Kang, S.; Kim, M. Surface Plasmon Resonance: A Versatile Technique for Biosensor Applications. Sensors 2015, 15, 10481– 10510, DOI: 10.3390/s150510481Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXptlKqurw%253D&md5=98cc17f36c89a34ab7db91932cbcb954Surface plasmon resonance: a versatile technique for biosensor applicationsNguyen, Hoang Hiep; Park, Jeho; Kang, Sebyung; Kim, MoonilSensors (2015), 15 (5), 10481-10510CODEN: SENSC9; ISSN:1424-8220. (MDPI AG)A review. Surface plasmon resonance (SPR) is a label-free detection method which has emerged during the last two decades as a suitable and reliable platform in clin. anal. for biomol. interactions. The technique makes it possible to measure interactions in real-time with high sensitivity and without the need of labels. This review article discusses a wide range of applications in optical-based sensors using either surface plasmon resonance (SPR) or surface plasmon resonance imaging (SPRI). Here we summarize the principles, provide examples, and illustrate the utility of SPR and SPRI through example applications from the biomedical, proteomics, genomics and bioengineering fields. In addn., SPR signal amplification strategies and surface functionalization are covered in the review.
- 14Reimhult, E.; Höök, F. Design of Surface Modifications for Nanoscale Sensor Applications. Sensors 2015, 15, 1635– 1675, DOI: 10.3390/s150101635Google Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2Mros1WisQ%253D%253D&md5=da99f5bcc143b6247a288ac9280852b9Design of surface modifications for nanoscale sensor applicationsReimhult Erik; Hook FredrikSensors (Basel, Switzerland) (2015), 15 (1), 1635-75 ISSN:.Nanoscale biosensors provide the possibility to miniaturize optic, acoustic and electric sensors to the dimensions of biomolecules. This enables approaching single-molecule detection and new sensing modalities that probe molecular conformation. Nanoscale sensors are predominantly surface-based and label-free to exploit inherent advantages of physical phenomena allowing high sensitivity without distortive labeling. There are three main criteria to be optimized in the design of surface-based and label-free biosensors: (i) the biomolecules of interest must bind with high affinity and selectively to the sensitive area; (ii) the biomolecules must be efficiently transported from the bulk solution to the sensor; and (iii) the transducer concept must be sufficiently sensitive to detect low coverage of captured biomolecules within reasonable time scales. The majority of literature on nanoscale biosensors deals with the third criterion while implicitly assuming that solutions developed for macroscale biosensors to the first two, equally important, criteria are applicable also to nanoscale sensors. We focus on providing an introduction to and perspectives on the advanced concepts for surface functionalization of biosensors with nanosized sensor elements that have been developed over the past decades (criterion (iii)). We review in detail how patterning of molecular films designed to control interactions of biomolecules with nanoscale biosensor surfaces creates new possibilities as well as new challenges.
- 15Waggoner, P. S.; Craighead, H. G. Micro- and Nanomechanical Sensors for Environmental, Chemical, and Biological Detection. Lab Chip 2007, 7, 1238– 1255, DOI: 10.1039/b707401hGoogle Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtVOrtL%252FE&md5=9713ef6c5678177a3fe1b897951b1d0eMicro- and nanomechanical sensors for environmental, chemical, and biological detectionWaggoner, Philip S.; Craighead, Harold G.Lab on a Chip (2007), 7 (10), 1238-1255CODEN: LCAHAM; ISSN:1473-0197. (Royal Society of Chemistry)A review. Micro- and nanoelectromech. systems, including cantilevers and other small scale structures, were studied for sensor applications. Accurate sensing of gaseous or aq. environments, chem. vapors, and biomols. were demonstrated using a variety of these devices that undergo static deflections or shifts in resonant frequency upon analyte binding. In particular, biol. detection of viruses, antigens, DNA, and other proteins is of great interest. While the majority of currently used detection schemes are reliant on biomarkers, such as fluorescent labels, time, effort, and chem. activity could be saved by developing an ultrasensitive method of label-free mass detection. Micro- and nanoscale sensors were effectively applied as label-free detectors. In the following, the authors review the technologies and recent developments in the field of micro- and nanoelectromech. sensors with particular emphasis on their application as biol. sensors and recent work towards integrating these sensors in microfluidic systems.
- 16Pitruzzello, G.; Krauss, T. F. Photonic crystal resonances for sensing and imaging. J. Opt. 2018, 20, 073004, DOI: 10.1088/2040-8986/aac75bGoogle Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXkvFant7Y%253D&md5=57ec9f410af4c4dd1b9a53c6ebb14202Photonic crystal resonances for sensing and imagingPitruzzello, Giampaolo; Krauss, Thomas F.Journal of Optics (Bristol, United Kingdom) (2018), 20 (7), 073004/1-073004/23CODEN: JOOPCA; ISSN:2040-8978. (IOP Publishing Ltd.)This review provides an insight into the recent developments of photonic crystal (PhC)-based devices for sensing and imaging, with a particular emphasis on biosensors. We focus on two main classes of devices, namely sensors based on PhC cavities and those on guided mode resonances (GMRs). This distinction is able to capture the richness of possibilities that PhCs are able to offer in this space. We present recent examples highlighting applications where PhCs can offer new capabilities, open up new applications or enable improved performance, with a clear emphasis on the different types of structures and photonic functions. We provide a crit. comparison between cavity-based devices and GMR devices by highlighting strengths and weaknesses. We also compare PhC technologies and their sensing mechanism to surface plasmon resonance, microring resonators and integrated interferometric sensors.
- 17Greenwood, D. β-Lactam Antibiotics—Cephalosporins. In Antibiotic and Chemotherapy, 9th ed.; Finch, R. G., Greenwood, D., Norrby, S. R., Whitely, R. J., Eds.; Saunders, 2010; Chapter 13, pp 170– 199.Google ScholarThere is no corresponding record for this reference.
- 18Qi, X.; Gunawan, P.; Xu, R.; Chang, M. W. Cefalexin-immobilized Multi-walled Carbon Nanotubes Show Strong Antimicrobial and Anti-adhesion Properties. Chem. Eng. Sci. 2012, 84, 552– 556, DOI: 10.1016/j.ces.2012.08.054Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1eiur3E&md5=28e493ae00303f1f415f16e19cb4cc88Cefalexin-immobilized multi-walled carbon nanotubes show strong antimicrobial and anti-adhesion propertiesQi, Xiaobao; Gunawan, Poernomo; Xu, Rong; Chang, Matthew WookChemical Engineering Science (2012), 84 (), 552-556CODEN: CESCAC; ISSN:0009-2509. (Elsevier Ltd.)Multi-walled carbon nanotubes (MWNTs) possess weak antimicrobial property. In this report, we demonstrate that the covalent immobilization of the antibiotic cefalexin via poly(ethylene glycol) as a linking agent improves the antimicrobial and anti-adhesive properties of MWNTs against both Gram-neg. bacteria (Escherichia coli and Pseudomonas aeruginosa) and Gram-pos. bacteria (Staphylococcus aureus and Bacillus subtilis). In particular, the MWNT-cefalexin composite showed 2-fold higher antimicrobial property than pristine MWNTs against S. aureus and B. subtilis. Moreover, the MWNT-cefalexin deposited film effectively inhibited cell adhesion. Given the simple, inexpensive procedures of our synthesis method, the MWNT-cefalexin composite has the potential to be used as an effective and economical antibacterial and anti-adhesion material for environmental and biomedical applications.
- 19Dreesen, L.; Silien, C.; Volcke, C.; Sartenaer, Y.; Thiry, P. A.; Peremans, A.; Grugier, J.; Marchand-Brynaert, J.; Brans, A.; Grubisic, S.; Joris, B. Adsorption Properties of the Penicillin Derivative DTPA on Gold Substrates. ChemPhysChem 2007, 8, 1071– 1076, DOI: 10.1002/cphc.200700087Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXlvVGksrg%253D&md5=69a58dbbd6567420aa36ed86fc230f7eAdsorption properties of the penicillin derivative DTPA on gold substratesDreesen, Laurent; Silien, Christophe; Volcke, Cedric; Sartenaer, Yannick; Thiry, Paul A.; Peremans, Andre; Grugier, Jerome; Marchand-Brynaert, Jacqueline; Brans, Alain; Grubisic, Stana; Joris, BernardChemPhysChem (2007), 8 (7), 1071-1076CODEN: CPCHFT; ISSN:1439-4235. (Wiley-VCH Verlag GmbH & Co. KGaA)Despite the large no. of articles and patents dealing with penicillin and other β-lactam antibiotics, there were no reports about the self-assembly of such substances as monolayers on gold surfaces. The main reason stems from the high reactivity of the β-lactam ring, which hinders the development of mols. possessing this entity together with a metal-anchoring function. Herein, the authors present the synthesis of a novel mol., 6-[(R,S)-5-(1,2-dithiolan-3-yl)pentanoyl-amino]-penicillanic acid (DTPA), which combines the β-lactam ring and a metal-anchoring group. Using spectroscopic tools, the authors demonstrate the chemisorption of this compd. on gold as self-assembled monolayers without any alteration of the penicillin pharmacophore and document its reactivity towards a penicillin-binding protein, BlaR-CTD. The authors' work is a preliminary step towards the development of new biosensors and well-ordered protein arrays, both based on the high affinity of penicillin for penicillin-binding proteins.
- 20Tarrat, N.; Benoit, M.; Giraud, M.; Ponchet, A.; Casanove, M. J. The Gold/Ampicillin Interface at the Atomic Scale. Nanoscale 2015, 7, 14515– 14524, DOI: 10.1039/c5nr03318gGoogle Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1Khs7vO&md5=7993e0105da92e28a43b20ecaf920fbfThe gold/ampicillin interface at the atomic scaleTarrat, N.; Benoit, M.; Giraud, M.; Ponchet, A.; Casanove, M. J.Nanoscale (2015), 7 (34), 14515-14524CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)In the fight against antibiotic resistance, gold nanoparticles (AuNP) with antibiotics grafted on their surfaces have been found to be potent agents. Ampicillin-conjugated AuNPs have been thus reported to overcome highly ampicillin-resistant bacteria. However, the structure at the at. scale of these hybrid systems remains misunderstood. In this paper, the structure of the interface between an ampicillin mol. AMP and three flat gold facets Au(111), Au(110) and Au(100) has been investigated with numerical simulations (dispersion-cor. DFT). Adsorption energies, bond distances and electron densities indicate that the adsorption of AMP on these facets goes through multiple partially covalent bonding. The stability of the AuNP/AMP nanoconjugates is explained by large adsorption energies and their potential antibacterial activity is discussed on the basis of the constrained spatial orientation of the grafted antibiotic.
- 21Padayatti, P. S.; Helfand, M. S.; Totir, M. A.; Carey, M. P.; Carey, P. R.; Bonomo, R. A.; van den Akker, F. High Resolution Crystal Structures of the trans-Enamine Intermediates Formed by Sulbactam and Clavulanic Acid and E166A SHV-1 β-Lactamase. J. Biol. Chem. 2005, 280, 34900– 34907, DOI: 10.1074/jbc.m505333200Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtVyks7%252FE&md5=248b3dd549e2b483428f7b29c13d967aHigh Resolution Crystal Structures of the trans-Enamine Intermediates Formed by Sulbactam and Clavulanic Acid and E166A SHV-1 β-LactamasePadayatti, Pius S.; Helfand, Marion S.; Totir, Monica A.; Carey, Marianne P.; Carey, Paul R.; Bonomo, Robert A.; van den Akker, FoccoJournal of Biological Chemistry (2005), 280 (41), 34900-34907CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Antibiotic resistance mediated by constantly evolving β-lactamases is a serious threat to human health. The mechanism of inhibition of these enzymes by therapeutic β-lactamase inhibitors is probed using a novel approach involving Raman microscopy and x-ray crystallog. We have presented here the high resoln. crystal structures of the β-lactamase inhibitors sulbactam and clavulanic acid bound to the deacylation-deficient E166A variant of SHV-1 β-lactamase. Our previous Raman measurements have identified the trans-enamine species for both inhibitors and were used to guide the soaking time and concn. to achieve full occupancy of the active sites. The two inhibitor-bound x-ray structures revealed a linear trans-enamine intermediate covalently attached to the active site Ser-70 residue. This intermediate was thought to play a key role in the transient inhibition of class A β-lactamases. Both the Raman and x-ray data indicated that the clavulanic acid intermediate is decarboxylated. When compared with our previously detd. tazobactam-bound inhibitor structure, our new inhibitor-bound structures revealed an increased disorder in the tail region of the inhibitors as well as in the enamine skeleton. The x-ray crystallog. observations correlated with the broadening of the O-C=C-N (enamine) sym. stretch Raman band near 1595 cm-1. Band broadening in the sulbactam and clavulanic acid intermediates reflected a heterogeneous conformational population that results from variations of torsional angles in the O-(C=O)-C=C=NH-C skeleton. These observations led us to conclude that the conformational stability of the trans-enamine form is crit. for their transient inhibitory efficacy.
- 22Prime, K. L.; Whitesides, G. M. Adsorption of Proteins onto Surfaces Containing End-attached Oligo(ethylene oxide): A Model System Using Self-assembled Monolayers. J. Am. Chem. Soc. 1993, 115, 10714– 10721, DOI: 10.1021/ja00076a032Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXmsVCrtbk%253D&md5=2bc4272cf29fc4109818160bea5f7f30Adsorption of proteins onto surfaces containing end-attached oligo(ethylene oxide): a model system using self-assembled monolayersPrime, Kevin L.; Whitesides, George M.Journal of the American Chemical Society (1993), 115 (23), 10714-21CODEN: JACSAT; ISSN:0002-7863.This paper reports a study of the adsorption of four proteins-fibrinogen, lysozyme, pyruvate kinase, and RNAse A-to self-assembled monolayers (SAMs) on gold. The SAMs examd. were derived from thiols of the structure HS(CH2)10R, where R was CH3, CH2OH, and oligo(ethylene oxide). Monolayers that contained a sufficiently large mole fraction of alkanethiolate groups terminated in oligo(ethylene oxide) chains resisted the kinetically irreversible, nonspecific adsorption of all four proteins. Longer chains of oligo(ethylene oxide) were resistant at lower mole fractions in the monolayer. Resistance to the adsorption of proteins increased with the length of the oligo(ethylene oxide) chain: the smallest mole fraction of chains that prevented adsorption was proportional to n-0.4, where n represents the no. of ethylene oxide units per chain. Termination of the oligo(ethylene oxide) chains with a methoxy group instead of a hydroxyl group had little or no effect on the amt. of protein adsorbed. The amt. of pyruvate kinase that adsorbed to mixed SAMs contg. hexa(ethylene oxide)-terminated chains depended upon the temp. When the mole fraction of oligo(ethylene oxide) groups in the monolayer was below the level needed to prevent adsorption, more pyruvate kinase adsorbed to the monolayer at 37°C than at 25°C. No difference was obsd. between adsorption at 25 and 4°C.
- 23Banerjee, I.; Pangule, R. C.; Kane, R. S. Antifouling Coatings: Recent Developments in the Design of Surfaces that Prevent Fouling by Proteins, Bacteria, and Marine Organisms. Adv. Mater. 2011, 23, 690– 718, DOI: 10.1002/adma.201001215Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVOmtLw%253D&md5=60430143bc3f7595c0f46731f168d224Antifouling Coatings: Recent Developments in the Design of Surfaces That Prevent Fouling by Proteins, Bacteria, and Marine OrganismsBanerjee, Indrani; Pangule, Ravindra C.; Kane, Ravi S.Advanced Materials (Weinheim, Germany) (2011), 23 (6), 690-718CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The major strategies for designing surfaces that prevent fouling due to proteins, bacteria, and marine organisms are reviewed. Biofouling is of great concern in numerous applications. The two major approaches to combat surface fouling are based on either preventing biofoulants from attaching or degrading them. While protein-resistant coatings may also resist bacterial attachment and subsequent biofilm formation, in order to overcome the fouling-mediated risk of bacterial infection it is highly desirable to design coatings that are bactericidal. Traditional techniques involve the design of coatings that release biocidal agents. However, the emergence of antibiotic- and silver-resistant pathogenic strains has necessitated the development of alternative strategies. Therefore, other techniques are being investigated. With regard to marine antifouling coatings, restrictions on the use of biocide-releasing coatings have made the generation of nontoxic antifouling surfaces more important. While considerable progress has been made in the design of antifouling coatings, ongoing research in this area should result in the development of even better antifouling materials in the future.
- 24Mehne, J.; Markovic, G.; Pröll, F.; Schweizer, N.; Zorn, S.; Schreiber, F.; Gauglitz, G. Characterisation of morphology of self-assembled PEG monolayers: a comparison of mixed and pure coatings optimised for biosensor applications. Anal. Bioanal. Chem. 2008, 391, 1783– 1791, DOI: 10.1007/s00216-008-2066-0Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXnsFakur8%253D&md5=bcce546491c8895c9cec7a194875e905Characterisation of morphology of self-assembled PEG monolayers: a comparison of mixed and pure coatings optimised for biosensor applicationsMehne, Jochen; Markovic, Goran; Proell, Florian; Schweizer, Nina; Zorn, Stefan; Schreiber, Frank; Gauglitz, GuenterAnalytical and Bioanalytical Chemistry (2008), 391 (5), 1783-1791CODEN: ABCNBP; ISSN:1618-2642. (Springer)For detection of low concns. of analytes in complex biol. matrixes using optical biosensors, a high surface loading with capture mols. and a low nonspecific binding of nonrelevant matrix mols. are essential. To tailor biosensor surfaces in such a manner, poly(ethylene glycols) (PEG) in varying lengths were immobilized covalently onto glass-type surfaces in different mixing ratios and concns., and were subsequently modified with three different kinds of receptors. The nonspecific binding of a model protein (ovalbumin, OVA) and the max. loading of the resp. analytes to these prepd. surfaces were monitored using label-free and time-resolved reflectometric interference spectroscopy (RIfS). The three different analytes used varied in size: 150 kDa for the anti-atrazine antibody, 60 kDa for streptavidin and 5 kDa for the 15-bp oligonucleotide. The authors investigated if the mixing of PEG in different lengths could increase the surface loadings of analyte mimicking a three-dimensional matrix as was found using dextrans as sensor coatings. In addn., the effect on the surface loading was investigated with regard to the size of the analyte mol. using such mixed PEGs on the sensor surface. For further characterization of the surface coatings, polarization modulation IR reflection absorption spectroscopy, at. force microscopy, and ellipsometry were applied.
- 25Unsworth, L. D.; Sheardown, H.; Brash, J. L. Polyethylene Oxide Surfaces of Variable Chain Density by Chemisorption of PEO-thiol on Gold: Adsorption of Proteins from Plasma Studied by Radiolabelling and Immunoblotting. Biomaterials 2005, 26, 5927– 5933, DOI: 10.1016/j.biomaterials.2005.03.010Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXlt1WgsLc%253D&md5=a6ef6d631ce2edae598789b2bc8f172aPolyethylene oxide surfaces of variable chain density by chemisorption of PEO-thiol on gold: Adsorption of proteins from plasma studied by radiolabelling and immunoblottingUnsworth, Larry D.; Sheardown, Heather; Brash, John L.Biomaterials (2005), 26 (30), 5927-5933CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)The mechanisms involved in the inhibition of protein adsorption by polyethylene oxide (PEO) are not completely understood, but it is believed that PEO chain length, chain d. and chain conformation all play a role. In this work, surfaces formed by chemisorption of PEO-thiol to gold were investigated: the effects of PEO chain d., chain length (600, 750, 2000 and 5000 MW) and end-group (-OH, -OCH3) on protein adsorption from plasma are reported. Similar to previous single protein adsorption studies (L.D. Unsworth et al., Langmuir 2005;21:1036-41) it was found that, of the different surfaces investigated, PEO layers formed from solns. near the cloud point adsorbed the lowest amt. of fibrinogen from plasma. Layers of hydroxyl-terminated PEO of MW 600 formed under these low soly. conditions showed almost complete suppression (vs. controls) of the Vroman effect, with 20±1 ng/cm2 adsorbed fibrinogen at the Vroman peak and 6.7±0.6 ng/cm2 at higher plasma concn. By comparison, Vroman peak adsorption was 70±20 and 50±3 ng/cm2, resp., for 750-OCH3 and 2000-OCH3 layers formed under low soly. conditions; adsorption on these surfaces at higher plasma concn. was 16±9 and 12±3 ng/cm2. Thus in addn. to the effect of soln. conditions noted previously, the results of this study also suggest a chain end group effect which inhibits fibrinogen adsorption to, and/or facilitates displacement from, hydroxyl terminated PEO layers. Fibrinogen adsorption from plasma was not significantly different for surfaces prepd. with PEO of mol. wt. 750 and 2000 when the chain d. was the same (∼0.5 chains/nm2) supporting the conclusion that chain d. may be the key property for suppression of protein adsorption. The proteins eluted from the surfaces after contact with plasma were investigated by SDS-PAGE and immunoblotting. A no. of proteins were detected on the various surfaces including fibrinogen, albumin, C3 and apolipoprotein A-I. The blot responses were zero or weak for all four proteins of the contact system; some complement activation was obsd. on all of the surfaces studied.
- 26Hinterwirth, H.; Kappel, S.; Waitz, T.; Prohaska, T.; Lindner, W.; Lämmerhofer, M. Quantifying Thiol Ligand Density of Self-Assembled Monolayers on Gold Nanoparticles by Inductively Coupled Plasma-Mass Spectrometry. ACS Nano 2013, 7, 1129– 1136, DOI: 10.1021/nn306024aGoogle Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFWrsbw%253D&md5=7bbb8884425a162715668ef87418ab27Quantifying Thiol Ligand Density of Self-Assembled Monolayers on Gold Nanoparticles by Inductively Coupled Plasma-Mass SpectrometryHinterwirth, Helmut; Kappel, Stefanie; Waitz, Thomas; Prohaska, Thomas; Lindner, Wolfgang; Laemmerhofer, MichaelACS Nano (2013), 7 (2), 1129-1136CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)Gold nanoparticles (GNPs) are often used as colloidal carriers in numerous applications owing to their low-cost and size-controlled prepn. as well as their straightforward surface functionalization with thiol contg. mols. forming self-assembling monolayers (SAM). The quantification of the ligand d. of such modified GNPs is tech. challenging, yet of utmost importance for quality control in many applications. In this contribution, a new method for the detn. of the surface coverage of GNPs with thiol contg. ligands is proposed. It makes use of the measurement of the gold-to-sulfur (Au/S) ratio by inductively coupled plasma mass spectrometry (ICP-MS) and its dependence on the nanoparticle diam. The simultaneous ICP-MS measurement of gold and sulfur was carefully validated and found to be a robust method with a relative std. uncertainty of lower than 10%. A major advantage of this method is the independence from sample prepn.; for example, sample loss during the washing steps is not affecting the results. To demonstrate the utility of the straightforward method, GNPs of different diams. were synthesized and derivatized on the surface with bifunctional (lipophilic) ω-mercapto-alkanoic acids and (hydrophilic) mercapto-poly(ethylene glycol) (PEG)n-carboxylic acids by self-assembling monolayer (SAM) formation. A size-independent but ligand-chain length-dependent ligand d. was found. The surface coverage increases from 4.3 to 6.3 mols. nm-2 with a decrease of ligand chain length from 3.52 to 0.68 nm. Furthermore, no significant difference between the surface coverage of hydrophilic and lipophilic ligands with approx. the same ligand length was found, indicating that steric hindrance is of more importance than, for example, intermol. strand interactions of Van der Waals forces as claimed in other studies.
- 27Chang, E. P.; Roncal-Herrero, T.; Morgan, T.; Dunn, K. E.; Rao, A.; Kunitake, J. A. M. R.; Lui, S.; Bilton, M.; Estroff, L. A.; Kröger, R.; Johnson, S.; Cölfen, H.; Evans, J. S. Synergistic Biomineralization Phenomena Created by a Combinatorial Nacre Protein Model System. Biochemistry 2016, 55, 2401– 2410, DOI: 10.1021/acs.biochem.6b00163Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XlvVCjs7c%253D&md5=7815c1adf9502a183e1b2706101f9037Synergistic Biomineralization Phenomena Created by a Combinatorial Nacre Protein Model SystemChang, Eric P.; Roncal-Herrero, Teresa; Morgan, Tamara; Dunn, Katherine E.; Rao, Ashit; Kunitake, Jennie A. M. R.; Lui, Susan; Bilton, Matthew; Estroff, Lara A.; Kroger, Roland; Johnson, Steven; Colfen, Helmut; Evans, John SpencerBiochemistry (2016), 55 (16), 2401-2410CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)In the nacre or aragonite layer of the mollusk shell, proteomes that regulate both the early stages of nucleation and nano-to-mesoscale assembly of nacre tablets from mineral nanoparticle precursors exist. Several approaches have been developed to understand protein-assocd. mechanisms of nacre formation, yet we still lack insight into how protein ensembles or proteomes manage nucleation and crystal growth. To provide addnl. insights, we have created a proportionally defined combinatorial model consisting of two nacre-assocd. proteins, C-RING AP7 (shell nacre, Haliotis rufescens) and pseudo-EF hand PFMG1 (oyster pearl nacre, Pinctada fucata), whose individual in vitro mineralization functionalities are well-documented and distinct from one another. Using SEM, flow cell scanning transmission electron microscopy, at. force microscopy, Ca(II) potentiometric titrns., and quartz crystal microbalance with dissipation monitoring quant. analyses, we find that both nacre proteins are functionally active within the same mineralization environments and, at 1:1 molar ratios, synergistically create calcium carbonate mesoscale structures with ordered intracryst. nanoporosities, extensively prolong nucleation times, and introduce an addnl. nucleation event. Further, these two proteins jointly create nanoscale protein aggregates or phases that under mineralization conditions further assemble into protein-mineral polymer-induced liq. precursor-like phases with enhanced ACC stabilization capabilities, and there is evidence of intermol. interactions between AP7 and PFMG1 under these conditions. Thus, a combinatorial model system consisting of more than one defined biomineralization protein dramatically changes the outcome of the in vitro biomineralization process.
- 28Davenport, M.; Mach, K. E.; Shortliffe, L. M. D.; Banaei, N.; Wang, T.-H.; Liao, J. C. New and developing diagnostic technologies for urinary tract infections. Nat. Rev. Urol. 2017, 14, 296– 310, DOI: 10.1038/nrurol.2017.20Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1czhslGntg%253D%253D&md5=ca102f0137ea34d7bb8e8a943ff1039bNew and developing diagnostic technologies for urinary tract infectionsDavenport Michael; Mach Kathleen E; Shortliffe Linda M Dairiki; Liao Joseph C; Banaei Niaz; Wang Tza-Huei; Liao Joseph CNature reviews. Urology (2017), 14 (5), 296-310 ISSN:.Timely and accurate identification and determination of the antimicrobial susceptibility of uropathogens is central to the management of UTIs. Urine dipsticks are fast and amenable to point-of-care testing, but do not have adequate diagnostic accuracy or provide microbiological diagnosis. Urine culture with antimicrobial susceptibility testing takes 2-3 days and requires a clinical laboratory. The common use of empirical antibiotics has contributed to the rise of multidrug-resistant organisms, reducing treatment options and increasing costs. In addition to improved antimicrobial stewardship and the development of new antimicrobials, novel diagnostics are needed for timely microbial identification and determination of antimicrobial susceptibilities. New diagnostic platforms, including nucleic acid tests and mass spectrometry, have been approved for clinical use and have improved the speed and accuracy of pathogen identification from primary cultures. Optimization for direct urine testing would reduce the time to diagnosis, yet these technologies do not provide comprehensive information on antimicrobial susceptibility. Emerging technologies including biosensors, microfluidics, and other integrated platforms could improve UTI diagnosis via direct pathogen detection from urine samples, rapid antimicrobial susceptibility testing, and point-of-care testing. Successful development and implementation of these technologies has the potential to usher in an era of precision medicine to improve patient care and public health.
- 29Geertsma, E. R.; Poolman, B. High-throughput cloning and expression in recalcitrant bacteria. Nat. Methods 2007, 4, 705– 707, DOI: 10.1038/nmeth1073Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXps12gsLc%253D&md5=8dda823cd44b8c30c973c10f4117f3a0High-throughput cloning and expression in recalcitrant bacteriaGeertsma, Eric R.; Poolman, BertNature Methods (2007), 4 (9), 705-707CODEN: NMAEA3; ISSN:1548-7091. (Nature Publishing Group)We developed a generic method for high-throughput cloning in bacteria that are less amenable to conventional DNA manipulations. The method involves ligation-independent cloning in an intermediary Escherichia coli vector, which is rapidly converted via vector-backbone exchange (VBEx) into an organism-specific plasmid ready for high-efficiency transformation. We demonstrated VBEx proof of principle for Lactococcus lactis, but the method can be adapted to all organisms for which plasmids are available.
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Compound synthesis and characterization, protein binding assay, PM-IRRAS, and additional QCM-D data (PDF)
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