Abstract
The evolution of drug resistance has a profound impact on human health. Candida glabrata is a leading human fungal pathogen that can rapidly evolve resistance to echinocandins, which target cell wall biosynthesis and are front-line therapeutics for Candida infections. Here, we provide the first global analysis of mutations accompanying the evolution of fungal drug resistance in a human host utilizing a series of C. glabrata isolates that evolved echinocandin resistance in a patient treated with the echinocandin caspofungin for recurring bloodstream candidemia. Whole genome sequencing identified a mutation in the drug target, FKS2, accompanying a major resistance increase, and 8 additional non-synonymous mutations. The FKS2-T1987C mutation was sufficient for echinocandin resistance, and associated with a fitness cost that was mitigated with further evolution, observed in vitro and in a murine model of systemic candidemia. A CDC6-A511G(K171E) mutation acquired before FKS2-T1987C(S663P), conferred a small resistance increase. Elevated dosage of CDC55, which acquired a C463T(P155S) mutation after FKS2-T1987C(S663P), ameliorated fitness. To discover strategies to abrogate echinocandin resistance, we focused on the molecular chaperone Hsp90 and downstream effector calcineurin. Genetic or pharmacological compromise of Hsp90 or calcineurin function reduced basal tolerance and resistance. Hsp90 and calcineurin were required for caspofungin-dependent FKS2 induction, providing a mechanism governing echinocandin resistance. A mitochondrial respiration-defective petite mutant in the series revealed that the petite phenotype does not confer echinocandin resistance, but renders strains refractory to synergy between echinocandins and Hsp90 or calcineurin inhibitors. The kidneys of mice infected with the petite mutant were sterile, while those infected with the HSP90-repressible strain had reduced fungal burden. We provide the first global view of mutations accompanying the evolution of fungal drug resistance in a human host, implicate the premier compensatory mutation mitigating the cost of echinocandin resistance, and suggest a new mechanism of echinocandin resistance with broad therapeutic potential.
Highlights
The emergence of drug resistance is an evolutionary process with a profound impact on human health
We harness whole genome sequencing to provide a global view of mutations that accumulate in C. glabrata during the evolution of echinocandin resistance in a human host
We reveal the first global portrait of antifungal resistance mutations that evolve in a human host, identify the first compensatory mutation that mitigates the cost of echinocandin resistance, and suggest a new mechanism of echinocandin resistance that can be exploited to treat life-threatening fungal infections
Summary
The emergence of drug resistance is an evolutionary process with a profound impact on human health. The emergence of drug resistance in fungal pathogens is of particular concern given the increasing incidence of invasive fungal infections, and the limited number of antifungal drugs. Fungi can cause life-threatening infectious disease in immunocompromised hosts, as well as in healthy humans, and the incidence of fungal bloodstream infections has increased by 207% in recent decades [6,7,8]. Fungi are eukaryotes and share close evolutionary relationships with their human hosts, which limits the number of drug targets that can be exploited to selectively kill fungal pathogens yet minimize host toxicity [1,3]. Even with current treatment options, mortality rates due to invasive fungal
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