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Drug interactions and the evolution of antibiotic resistance

Abstract

Large-scale, systems biology approaches now allow us to systematically map synergistic and antagonistic interactions between drugs. Consequently, drug antagonism is emerging as a powerful tool to study biological function and relatedness between cellular components as well as to uncover mechanisms of drug action. Furthermore, theoretical models and new experiments suggest that antagonistic interactions between antibiotics can counteract the evolution of drug resistance.

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Figure 1: A functional relationship between pathways can be revealed by the direct epistasis link between them and by the similarity of their epistasis interaction patterns with other pathways.
Figure 2: Suppressive drug combinations can reverse selection for resistance.
Figure 3: Drug interactions affect the mutant selection window.
Figure 4: Evolution in various antibiotic combinations reveals an accelerated rate of adaptation in synergistic drug pairs.

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Acknowledgements

We thank A. DeLuna, J.-B. Michel, R. Chait, N. Shoresh and T. Bollenbach for helpful discussion and comments on the manuscript. R. Chait contributed many of the figures for Box 1. This work was supported in part by a National Institutes of Health postdoctoral fellowship to P.J.Y., by National Science Foundation and National Defense Science and Engineering graduate fellowships to A.P.A. and by National Institutes of Health Grant R01GM081617 to R.K.

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Correspondence to Roy Kishony.

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Yeh, P., Hegreness, M., Aiden, A. et al. Drug interactions and the evolution of antibiotic resistance. Nat Rev Microbiol 7, 460–466 (2009). https://doi.org/10.1038/nrmicro2133

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