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The Continuing Challenge of Metallo-?-Lactamase Inhibition: Mechanism Matters.

ABSTRACT: Metallo-?-lactamases (MBLs) are a significant clinical problem because they hydrolyze and inactivate nearly all ?-lactam-containing antibiotics. These 'lifesaving drugs' constitute >50% of the available contemporary antibiotic arsenal. Despite the global spread of MBLs, MBL inhibitors have not yet appeared in clinical trials. Most MBL inhibitors target active site zinc ions and vary in mechanism from ternary complex formation to metal ion stripping. Importantly, differences in mechanism can impact pharmacology in terms of reversibility, target selectivity, and structure-activity relationship interpretation. This review surveys the mechanisms of MBL inhibitors and describes methods that determine the mechanism of inhibition to guide development of future therapeutics.

SUBMITTER: Ju LC

PROVIDER: S-EPMC6005755 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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The Continuing Challenge of Metallo-β-Lactamase Inhibition: Mechanism Matters.

Ju Lin-Cheng LC Cheng Zishuo Z Fast Walter W Bonomo Robert A RA Crowder Michael W MW

Trends in pharmacological sciences 20180418 7

Metallo-β-lactamases (MBLs) are a significant clinical problem because they hydrolyze and inactivate nearly all β-lactam-containing antibiotics. These 'lifesaving drugs' constitute >50% of the available contemporary antibiotic arsenal. Despite the global spread of MBLs, MBL inhibitors have not yet appeared in clinical trials. Most MBL inhibitors target active site zinc ions and vary in mechanism from ternary complex formation to metal ion stripping. Importantly, differences in mechanism can impa ...[more]

PMID: 29680579

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Metallo-?-Lactamase Inhibitors Inspired on Snapshots from the Catalytic Mechanism.

Project description:?-Lactam antibiotics are the most widely prescribed antibacterial drugs due to their low toxicity and broad spectrum. Their action is counteracted by different resistance mechanisms developed by bacteria. Among them, the most common strategy is the expression of ?-lactamases, enzymes that hydrolyze the amide bond present in all ?-lactam compounds. There are several inhibitors against serine-?-lactamases (SBLs). Metallo-?-lactamases (MBLs) are Zn(II)-dependent enzymes able to hydrolyze most ?-lactam antibiotics, and no clinically useful inhibitors against them have yet been approved. Despite their large structural diversity, MBLs have a common catalytic mechanism with similar reaction species. Here, we describe a number of MBL inhibitors that mimic different species formed during the hydrolysis process: substrate, transition state, intermediate, or product. Recent advances in the development of boron-based and thiol-based inhibitors are discussed in the light of the mechanism of MBLs. We also discuss the use of chelators as a possible strategy, since Zn(II) ions are essential for substrate binding and catalysis.

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Structural Basis of Metallo-β-Lactamase Inhibition by Captopril Stereoisomers.

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Structural basis of metallo-β-lactamase, serine-β-lactamase and penicillin-binding protein inhibition by cyclic boronates.

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Metallo-?-lactamase structure and function.

Project description:?-Lactam antibiotics are the most commonly used antibacterial agents and growing resistance to these drugs is a concern. Metallo-?-lactamases are a diverse set of enzymes that catalyze the hydrolysis of a broad range of ?-lactam drugs including carbapenems. This diversity is reflected in the observation that the enzyme mechanisms differ based on whether one or two zincs are bound in the active site that, in turn, is dependent on the subclass of ?-lactamase. The dissemination of the genes encoding these enzymes among Gram-negative bacteria has made them an important cause of resistance. In addition, there are currently no clinically available inhibitors to block metallo-?-lactamase action. This review summarizes the numerous studies that have yielded insights into the structure, function, and mechanism of action of these enzymes.

| S-EPMC3970115 | biostudies-literature

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Distinct Inhibition Modes of New Delhi Metallo-β-lactamase-1 Revealed by NMR Spectroscopy.

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| S-EPMC10052233 | biostudies-literature

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