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Target protection as a key antibiotic resistance mechanism

Abstract

Antibiotic resistance is mediated through several distinct mechanisms, most of which are relatively well understood and the clinical importance of which has long been recognized. Until very recently, neither of these statements was readily applicable to the class of resistance mechanism known as target protection, a phenomenon whereby a resistance protein physically associates with an antibiotic target to rescue it from antibiotic-mediated inhibition. In this Review, we summarize recent progress in understanding the nature and importance of target protection. In particular, we describe the molecular basis of the known target protection systems, emphasizing that target protection does not involve a single, uniform mechanism but is instead brought about in several mechanistically distinct ways.

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Fig. 1: Overview of target protection types.
Fig. 2: Protection of ribosomes from tetracycline by Tet(M).
Fig. 3: Ribosomal protection against antibiotics mediated by the ARE ABC-F proteins.
Fig. 4: Target protection mediated by FusB-type proteins.
Fig. 5: Proposed mechanism of target protection by HflXr proteins.
Fig. 6: Evolution of target protection proteins within the elongation factor 2 and ABC-F families of translation factors.

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Acknowledgements

Work on ribosome protection by the D.N.W. group is supported by Deutsche Forschungsgemeinschaft grants (WI3285/8-1 to D.N.W.), and studies in A.J.O.’s laboratory have been supported by the UK Biotechnology and Biological Sciences Research Council (grants BB/H018433/1 and BB/F016603/1). Antibiotic resistance studies in the D.N.W. and V.H. groups are also supported by the Deutsche Zentrum für Luft- und Raumfahrt (DLR01Kl1820 to D.N.W) and the Swedish Research Council (2018-00956 to V.H.) within the RIBOTARGET consortium under the frame of JPIAMR. The Swedish Research Council supports V.H. and G.C.A. (2017-03783 to V.H. and 2015-04746 and 2019-01085 to G.C.A.). Additional support to V.H. comes from the Ragnar Söderbergs Stiftelse, the European Regional Development Fund through the Centre of Excellence for Molecular Cell Engineering, Molecular Infection Medicine Sweden, and the Estonian Science Foundation (IUT2-22). G.C.A. is also supported by the Carl Tryggers Stiftelse förVetenskaplig Forskning (CTS 19:24), Kempestiftelserna(SMK-1858.3), Jeanssons Stiftelser, the Umeå Centre for Microbial Research gender policy programme and Umeå Universitet Insamlingsstiftelsen för Medicinsk Forskning.

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A.J.O. and D.N.W. led the drafting of the manuscript, with substantial input from the other authors.

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Correspondence to Daniel N. Wilson or Alex J. O’Neill.

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Glossary

GTPases

Enzymes that bind GTP and hydrolyse it to GDP, and play a role in diverse cellular processes.

Shine–Dalgarno helix

A short helix between the Shine–Dalgarno sequence present in the 5′ untranslated region of the mRNA and the anti-Shine–Dalgarno sequence present at the 3′ end of the 16S ribosomal RNA that promotes translation initiation.

Type II topoisomerases

ATP-dependent enzymes that alter DNA topology to manage chromosome segregation and DNA supercoiling.

Clinical breakpoints

Antibiotic susceptibility levels used to distinguish bacterial infections for which antibiotic treatment is likely to succeed from those for which it will likely fail.

GDPNP

5ʹ-Guanylyl imidodiphosphate, which is a non-hydrolysable GTP analogue.

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Wilson, D.N., Hauryliuk, V., Atkinson, G.C. et al. Target protection as a key antibiotic resistance mechanism. Nat Rev Microbiol 18, 637–648 (2020). https://doi.org/10.1038/s41579-020-0386-z

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