Interplay between β-lactamases and new β-lactamase inhibitors

Abstract

Resistance to β-lactam antibiotics in Gram-negative bacteria is commonly associated with production of β-lactamases, including extended-spectrum β-lactamases (ESBLs) and carbapenemases belonging to different molecular classes: those with a catalytically active serine and those with at least one active-site Zn2+ to facilitate hydrolysis. To counteract the hydrolytic activity of these enzymes, combinations of a β-lactam with a β-lactamase inhibitor (BLI) have been clinically successful. However, some β-lactam–BLI combinations have lost their effectiveness against prevalent Gram-negative pathogens that produce ESBLs, carbapenemases or multiple β-lactamases in the same organism. In this Review, descriptions are provided for medically relevant β-lactamase families and various BLI combinations that have been developed or are under development. Recently approved inhibitor combinations include the inhibitors avibactam and vaborbactam of the diazabicyclooctanone and boronic acid inhibitor classes, respectively, as new scaffolds for future inhibitor design.

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Fig. 1: Structures of β-lactams and β-lactamase inhibitors.
Fig. 2: General reaction pathway for the interaction of a β-lactam with penicillin-interactive enzymes.
Fig. 3: General mechanism of hydrolysis of β-lactams for serine and metallo-β-lactamases.
Fig. 4: General reaction mechanism for inhibition of a β-lactamase by a mechanism-based β-lactamase inhibitor.

Change history

  • 29 May 2019

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

  • 30 April 2019

    In figure 1 of the above article, the structure of ETX2514 was missing a double bond and methyl group. This has now been corrected in the PDF and online. The publisher apologizes to the authors and to the readers for this error.

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Nature Reviews Microbiology thanks R. A. Bonomo, D. Shlaes and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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K.B. and P.A.B. researched data for the article, made substantial contributions to discussions of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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The authors declare competing interests. K.B. serves as an independent consultant for pharmaceutical and biotechnology companies that discover and develop antimicrobial agents. P.A.B. is an independent consultant for companies that work on antibacterial agents. No support or input for the manuscript was provided by any of the companies for which K.B. or P.A.B. consult.

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Glossary

Penicillin-binding proteins

(PBPs). Bacterial cell wall synthesizing enzymes that are the killing targets of β-lactam antibiotics.

β-Lactamases

Bacterial enzymes that hydrolyse β-lactam bonds in β-lactam-containing antibiotics.

Integrons

Genetic elements, often including resistance determinants, that can be inserted into or excised from bacterial DNA.

Porin proteins

Bacterial proteins that form channels through the outer membrane of Gram-negative bacteria to allow the entry and exit of small molecules from the periplasmic space of the cell.

Hollow fibre model

An in vitro pharmacodynamics model that allows bacteria inside a porous membrane to be exposed to varying drug concentrations in a dynamic system that can be programmed to mimic human dosing regimens.

Stringent response

Refers to the reaction of a bacterial cell to environmental stress.

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Bush, K., Bradford, P.A. Interplay between β-lactamases and new β-lactamase inhibitors. Nat Rev Microbiol 17, 295–306 (2019). https://doi.org/10.1038/s41579-019-0159-8

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