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Molecular mechanisms of antibiotic resistance revisited

Abstract

Antibiotic resistance is a global health emergency, with resistance detected to all antibiotics currently in clinical use and only a few novel drugs in the pipeline. Understanding the molecular mechanisms that bacteria use to resist the action of antimicrobials is critical to recognize global patterns of resistance and to improve the use of current drugs, as well as for the design of new drugs less susceptible to resistance development and novel strategies to combat resistance. In this Review, we explore recent advances in understanding how resistance genes contribute to the biology of the host, new structural details of relevant molecular events underpinning resistance, the identification of new resistance gene families and the interactions between different resistance mechanisms. Finally, we discuss how we can use this information to develop the next generation of antimicrobial therapies.

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Fig. 1: Overview of the molecular mechanisms of antibiotic resistance.
Fig. 2: Structure and entry channels of RND efflux systems.
Fig. 3: Antibiotic resistance via target protection, drug inactivation and target bypass.

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J.M.A.B., E.M.D., E.T., P.S., M.S.G., I.A. and M.A.W. researched data for the article. J.M.A.B. and M.A.W. contributed substantially to discussion of the content. J.M.A.B., E.M.D., E.T., P.S., M.S.G., I.A. and M.A.W. wrote the article. J.M.A.B., E.M.D., E.T., P.S. and M.A.W. reviewed and/or edited the manuscript before submission.

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Correspondence to Mark A. Webber or Jessica M. A. Blair.

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Nature Reviews Microbiology thanks the anonymous reviewers for their contribution to the peer review of this work.

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Related links

Beta Lactamase Database: http://www.bldb.eu

Glossary

β-Lactamase

Enzymes produced by bacteria that degrade β-lactam antibiotics.

Epistasis

Where a mutation can exert a phenotypic effect but only in concert with other genes, making the impact conditional on the genetic background of where it occurs.

Horizontal gene transfer

The movement of genetic information between bacterial cells.

Insertion sequences

Small pieces of DNA that encode their own recombination machinery and can move within or between genomes.

Minimum inhibitory concentration

(MIC). The lowest concentration of antibiotic that prevents growth of bacteria.

Topoisomerases

Essential enzymes involved in DNA replication.

Two-component system

A system that allows bacteria to respond to specific environmental stimuli. Usually, it consists of a membrane-bound histidine kinase that senses the stimuli and activates a response regulator that alters the expression of relevant genes.

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Darby, E.M., Trampari, E., Siasat, P. et al. Molecular mechanisms of antibiotic resistance revisited. Nat Rev Microbiol (2022). https://doi.org/10.1038/s41579-022-00820-y

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