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Targeting virulence: can we make evolution-proof drugs?

Abstract

Antivirulence drugs are a new type of therapeutic drug that target virulence factors, potentially revitalising the drug-development pipeline with new targets. As antivirulence drugs disarm the pathogen, rather than kill or halt pathogen growth, it has been hypothesized that they will generate much weaker selection for resistance than traditional antibiotics. However, recent studies have shown that mechanisms of resistance to antivirulence drugs exist, seemingly damaging the 'evolution-proof' claim. In this Opinion article, we highlight a crucial distinction between whether resistance can emerge and whether it will spread to a high frequency under drug selection. We argue that selection for resistance can be reduced, or even reversed, using appropriate combinations of target and treatment environment, opening a path towards the development of evolutionarily robust novel therapeutics.

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Figure 1: The effects of virulence factors on fitness and virulence in different environments.
Figure 2: Predicted selection on resistance to antivirulence therapeutics.
Figure 3: The mechanistic target of the quorum-sensing inhibitor influences the strength of selection for resistance.

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Acknowledgements

The authors thank D. Cornforth, P. Vale, R. Kümmerli, A. Ross-Gillespie, R. Fitzgerald and three anonymous reviewers for comments and discussion. S.P.B. was funded by the Wellcome Trust, UK (grant number WT082273), and the Engineering and Physical Sciences Research Council (EPSRC), UK (grant number EP/H032436/1). S.P.D. was funded by the Royal Society, UK, and the Natural Environment Research Council (NERC), UK (grant number NE/J007064/1). R.C.A. was funded by the Natural Environment Research Council (NERC).

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Allen, R., Popat, R., Diggle, S. et al. Targeting virulence: can we make evolution-proof drugs?. Nat Rev Microbiol 12, 300–308 (2014). https://doi.org/10.1038/nrmicro3232

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