Topics

Harnessing β-Lactam Antibiotics for Illumination of the Activity of Penicillin-Binding Proteins in Bacillus subtilis.

08:00 EDT 10th March 2020 | BioPortfolio

Summary of "Harnessing β-Lactam Antibiotics for Illumination of the Activity of Penicillin-Binding Proteins in Bacillus subtilis."

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.

Affiliation

Journal Details

This article was published in the following journal.

Name: ACS chemical biology
ISSN: 1554-8937
Pages:

Links

DeepDyve research library

PubMed Articles [19733 Associated PubMed Articles listed on BioPortfolio]

β-Lactam resistance development affects binding of penicillin-binding proteins (PBPs) of Clostridium perfringens to the fluorescent penicillin, BOCILLIN FL.

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...

Synthesis and investigation of inhibitory activities of imidazole derivatives against the metallo-β-lactamase IMP-1.

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...

A Closer Look at Penicillin Allergy History: Systematic Review and Meta-analysis of Tolerance to Drug Challenge.

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...

ß-lactam antibiotics resistance in Latin American countries.

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...

Metallocenyl 7-ACA Conjugates: Antibacterial Activity Studies and Atomic-Resolution X-ray Crystal Structure with CTX-M β-Lactamase.

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 ...

Clinical Trials [6331 Associated Clinical Trials listed on BioPortfolio]

Penicillin Allergy Testing and Resensitization Rate

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. ...

Outcomes of Patients Not Responding to Antibiotics in the Community

A study to report the outcomes of patients who fail to respond to beta-lactam and macrolide antibiotics in the community

Minimally Invasive Sensing of Beta-lactam Antibiotics

This study is an in-house feasibility study of a microneedle biosensor developed within Imperial College London.

Therapeutic Drug Monitoring and Continuous Infusion of Beta-lactam Antibiotics in Patients With Bacteraemia

The study investigates whether Therapeutic Drug Monitoring (TDM) and continuous infusion (CI) of beta-lactam antibiotics optimises target concentrations in patients with bacteraemia.

Closed-loop Control of Penicillin Delivery

This study is an in-house feasibility study of penicillin biosensor technology linked with closed-loop control for the automated delivery of penicillin antibiotics.

Medical and Biotech [MESH] Definitions

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.

Quick Search


DeepDyve research library

Relevant Topic

Assays
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. ...


Searches Linking to this Article