Uncovering actionable trade-offs of antifungal resistance in a yeast pathogen.

The increasing prevalence of antifungal resistance represents a major clinical challenge. To explore potential new therapeutic avenues, we investigated fitness trade-offs associated with azole and echinocandin resistance in Nakaseomyces glabratus (syn. Candida glabrata), a priority yeast pathogen showing growing incidence of drug and multidrug resistance. For this, we comprehensively phenotyped a large collection (n = 77) of azole- and echinocandin-resistant strains to uncover resistance-associated stress sensitivity trade-offs. Our results show that increased stress sensitivity is a common trade-off of drug resistance in this species, with 98% of resistant strains exhibiting reduced fitness under at least one of six assayed stresses. Despite the diversity of genetic backgrounds and resistance mechanisms represented by our collection, we identified consistent trends in some resistance-associated vulnerabilities. Using multivariate modeling we uncovered complex genetic interactions underlying these trade-offs. As a proof of concept for therapeutic potential, we experimentally validated the inhibitory effects of targeting some fitness trade-offs. Cyclosporin A selectively inhibited anidulafungin-resistant strains, while NaCl effectively suppressed the emergence of fluconazole resistance. This study highlights the widespread occurrence of fitness costs associated with antifungal resistance and emphasizes their potential as a novel therapeutic strategy against this growing threat.