| Summary: | 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.
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