Molecular mechanisms of antibiotic resistance

Key Points

  • Antibiotic resistance is a global health emergency.

  • Resistance mechanisms exist for all current antibiotics, and few new drugs are in development.

  • Resistance can occur via a reduction in the intracellular concentration of drug, by target site alteration or protection and by the direct inactivation of antibiotics.

  • The mobilization of resistance genes into pathogens is making the treatment of severe infections challenging owing to a lack of effective antibiotics.

  • Our understanding of the molecular mechanisms of resistance has recently increased as a result of advances in systems biology, genomics and structural biology.

  • New knowledge about antibiotic resistance should be used to inform the design of novel therapeutic agents that might not be subject to, or can circumvent, mechanisms of resistance.

Abstract

Antibiotic-resistant bacteria that are difficult or impossible to treat are becoming increasingly common and are causing a global health crisis. Antibiotic resistance is encoded by several genes, many of which can transfer between bacteria. New resistance mechanisms are constantly being described, and new genes and vectors of transmission are identified on a regular basis. This article reviews recent advances in our understanding of the mechanisms by which bacteria are either intrinsically resistant or acquire resistance to antibiotics, including the prevention of access to drug targets, changes in the structure and protection of antibiotic targets and the direct modification or inactivation of antibiotics.

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Figure 1: Intrinsic mechanisms of resistance.
Figure 2: Pathways regulating multidrug efflux.
Figure 3: Target site changes.
Figure 4: Direct interactions with antibiotics.

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Acknowledgements

The authors would like to acknowledge the Medical Research Council (MRC), Biotechnology and Biological Sciences Research Council (BBSRC), Royal Society, Department for Environment, Food and Rural Affairs (DEFRA) and the National Institute for Health Research (NIHR) for funding their research.

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Glossary

Enoyl-ACP reductase

An enzyme key in the production of fatty acids which is the target for triclosan.

Lipopeptide

A natural or semi-synthetic fatty acid-linked peptide chain that targets the cell membrane (for example, daptomycin).

Glycopeptide

A natural or semi-synthetic amino sugar-linked peptide chain that targets terminal D-Ala-D-Ala dipeptides (for example, vancomycin).

β-lactams

An important class of antibiotics, members of which contain a β-lactam ring and inhibit peptidoglycan synthesis by covalent binding to the active-site Ser of penicillin-binding proteins. β-lactam subclasses include carbapenems, cephalosporins, penicillins, monobactams and clavams.

Fluoroquinolones

Synthetic compounds that target topoisomerases. Examples include nalidixic acid and ciprofloxacin.

Aminoglycosides

Natural or semi-synthetic amino sugars that target translation by binding to the 30S subunit of the ribosome. Examples include gentamicin, tobramycin, streptomycin and kanamycin.

Extended-spectrum β-lactamases

(ESBLs). β-lactamase enzymes that are able to hydrolyse extended-spectrum oxyimino cephalosporins.

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Blair, J., Webber, M., Baylay, A. et al. Molecular mechanisms of antibiotic resistance. Nat Rev Microbiol 13, 42–51 (2015). https://doi.org/10.1038/nrmicro3380

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