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Selective chemical probes enable individual investigation of penicillin-binding proteins (PBPs) and provide critical information about their enzymatic activity with spatial and temporal resolution. To identify scaffolds for novel probes to study peptidoglycan biosynthesis in Bacillus subtilis, we evaluated the PBP inhibition profiles of 21 β-lactam antibiotics from different structural subclasses using a fluorescence-based assay. Most compounds readily labeled PBP1, PBP2a, PBP2b or PBP4. Almost all penicillin scaffolds were co-selective for all or combinations of PBP2a, 2b and 4. Cephalosporins, on the other hand, possessed the lowest IC50 values for PBP1 alone or along with PBP4 (ceftriaxone, cefoxitin), 2b (cefotaxime) or 2a, 2b and 4 (cephalothin). Overall, five selective inhibitors for PBP1 (aztreonam, faropenem, piperacillin, cefuroxime and cefsulodin), one selective inhibitor for PBP5 (6-aminopenicillanic acid) and various co-selective inhibitors for other PBPs in B. subtilis were discovered. Surprisingly, carbapenems strongly inhibited PBP3, formerly shown to have low affinity for β-lactams and speculated to be involved in resistance in B. subtilis. To investigate the specific roles of PBP3, we developed activity-based probes based on the meropenem core and utilized them to monitor the activity of PBP3 in living cells. We showed that PBP3 activity localizes as patches in single cells and concentrates as a ring at the septum and the division site during the cell growth cycle. Our activity-based approach enabled spatial resolution of the transpeptidation activity of individual PBPs in this model microorganism, which was not possible with previous chemical and biological approaches.
This article was published in the following journal.
Name: ACS chemical biology
Alteration in the binding of bacterial penicillin-binding proteins (PBPs) to β-lactams is important in the development of drug resistance. The PBPs of wild type Clostridium perfringens ATCC 13124 and...
Mutations in bacteria can result in antibiotic resistance due to the overuse or abuse of β-lactam antibiotics. One strategy which bacteria can become resistance toward antibiotics is secreting of met...
True allergy to penicillin is rare, despite the high frequency with which it is reported. While most patients reporting penicillin allergy are not prone to anaphylaxis, it is not currently known what...
Ever since antimicrobial activity was observed at the end of the XIX century and antibiotics were produced on a large scale in the 40s, microorganisms have developed multiple resistance mechanisms, ma...
Here, we report the antibacterial properties of two metallocenyl (ferrocenyl and ruthenocenyl) 7-aminocephalosporanic acid (7-ACA) antibiotic bioorganometallic conjugates. Continuing a trend we found ...
Penicillin is one of the earliest discovered antibiotics and a drug of choice for several infections. Up to 10 to 20% of all patients in clinical trial are labeled as penicillin allergic. ...
A study to report the outcomes of patients who fail to respond to beta-lactam and macrolide antibiotics in the community
This study is an in-house feasibility study of a microneedle biosensor developed within Imperial College London.
The study investigates whether Therapeutic Drug Monitoring (TDM) and continuous infusion (CI) of beta-lactam antibiotics optimises target concentrations in patients with bacteraemia.
This study is an in-house feasibility study of penicillin biosensor technology linked with closed-loop control for the automated delivery of penicillin antibiotics.
Nonsusceptibility of bacteria to the action of the beta-lactam antibiotics. Mechanisms responsible for beta-lactam resistance may be degradation of antibiotics by BETA-LACTAMASES, failure of antibiotics to penetrate, or low-affinity binding of antibiotics to targets.
A beta-lactamase inhibitor with very weak antibacterial action. The compound prevents antibiotic destruction of beta-lactam antibiotics by inhibiting beta-lactamases, thus extending their spectrum activity. Combinations of sulbactam with beta-lactam antibiotics have been used successfully for the therapy of infections caused by organisms resistant to the antibiotic alone.
Bacterial proteins that share the property of binding irreversibly to PENICILLINS and other ANTIBACTERIAL AGENTS derived from LACTAMS. The penicillin-binding proteins are primarily enzymes involved in CELL WALL biosynthesis including MURAMOYLPENTAPEPTIDE CARBOXYPEPTIDASE; PEPTIDE SYNTHASES; TRANSPEPTIDASES; and HEXOSYLTRANSFERASES.
Monocyclic, bacterially produced or semisynthetic beta-lactam antibiotics. They lack the double ring construction of the traditional beta-lactam antibiotics and can be easily synthesized.
A group of beta-lactam antibiotics in which the sulfur atom in the thiazolidine ring of the penicillin molecule is replaced by a carbon atom. THIENAMYCINS are a subgroup of carbapenems which have a sulfur atom as the first constituent of the side chain.
An assay is an analytic procedure for qualitatively assessing or quantitatively measuring the presence or amount or the functional activity of a target entity. This can be a drug or biochemical substance or a cell in an organism or organic sample. ...