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Hill JA, O'Meara TR, Cowen LE. Fitness Trade-Offs Associated with the Evolution of Resistance to Antifungal Drug Combinations. Cell Rep. 2015;10(5):809-819doi: 10.1016/j.celrep.2015.01.009.
Hill, J. A., O'Meara, T. R., & Cowen, L. E. (2015). Fitness Trade-Offs Associated with the Evolution of Resistance to Antifungal Drug Combinations. Cell reports, 10(5), 809-819. https://doi.org/10.1016/j.celrep.2015.01.009
Hill, Jessica A, et al. "Fitness Trade-Offs Associated with the Evolution of Resistance to Antifungal Drug Combinations." Cell reports vol. 10,5 (2015): 809-819. doi: https://doi.org/10.1016/j.celrep.2015.01.009
Hill JA, O'Meara TR, Cowen LE. Fitness Trade-Offs Associated with the Evolution of Resistance to Antifungal Drug Combinations. Cell Rep. 2015 Feb 10;10(5):809-819. doi: 10.1016/j.celrep.2015.01.009. Epub 2015 Feb 05. PMID: 25660029.
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Cell Rep. 2015 Feb 10;10(5):809-819. doi: 10.1016/j.celrep.2015.01.009. Epub 2015 Feb 05.

Fitness Trade-Offs Associated with the Evolution of Resistance to Antifungal Drug Combinations.

Cell reports

Jessica A Hill, Teresa R O'Meara, Leah E Cowen

Affiliations

  1. Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
  2. Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada. Electronic address: [email protected].

PMID: 25660029 DOI: 10.1016/j.celrep.2015.01.009

Abstract

The evolution of drug resistance threatens human health worldwide. An emerging strategy to mitigate drug resistance is combination therapy. The fate of multidrug-resistant pathogens depends on their fitness relative to susceptible counterparts, yet the fitness consequences of multidrug resistance remain enigmatic. Here, we dissect fitness consequences of the evolution of resistance to antifungal drug combinations in the leading human fungal pathogen, Candida albicans. We focus on the most widely deployed antifungals, the azoles, and inhibitors of the molecular chaperone Hsp90 and protein phosphatase calcineurin, which regulate cellular stress responses required for azole resistance. We find tradeoffs such that adaptation to drug combinations is associated with reduced fitness in distinct environments, including those relevant to the human host. We identify mutations associated with fitness tradeoffs in clinical isolates and that influence morphogenesis, a key virulence trait. Thus, we delineate evolutionary constraints that may minimize the evolution of resistance to antifungal combinations.

Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

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