Narrow mutational signatures drive acquisition of multidrug resistance in the fungal pathogen Candida glabrata

Abstract

Fungal infections are a growing medical concern, in part due to increased resistance to one or multiple antifungal drugs. However, the evolutionary processes underpinning the acquisition of antifungal drug resistance are poorly understood. Here, we used experimental microevolution to study the adaptation of the yeast pathogen Candida glabrata to fluconazole and anidulafungin, two widely used antifungal drugs with different modes of action. Our results show widespread ability of rapid adaptation to one or both drugs. Resistance, including multidrug resistance, is often acquired at moderate fitness costs and mediated by mutations in a limited set of genes that are recurrently and specifically mutated in strains adapted to each of the drugs. Importantly, we uncover a dual role of ERG3 mutations in resistance to anidulafungin and cross-resistance to fluconazole in a subset of anidulafungin-adapted strains. Our results shed light on the mutational paths leading to resistance and cross-resistance to antifungal drugs.

The authors thank Ester Saus, Jesse Willis, and Cinta Pegueroles for their help and technical assistance with some of the analyses. M.A.S.-T. received a predoctoral fellowship from the ‘‘Caixa’’ Foundation (LCF/BQ/DR19/11740023). The T.G. group acknowledges support from the Spanish Ministry of Science and Innovation grant no. PGC2018-099921-B-I00, cofounded by the European Regional Development Fund (ERDF); from the CERCA Programme/Generalitat de Catalunya; from the Catalan Research Agency (AGAUR) SGR423; the European Union’s Horizon 2020 research and innovation program under grant agreement no. ERC-2016-724173; and the Marie Sk1odowska-Curie grant agreement no. H2020-MSCA-IF-2017-793699. The group also receives support from an INB grant (PT17/0009/0023-ISCIII-SGEFI/ERDF). The Bioactive Microbial Metabolites research platform (BiMM) is supported by grants K3- G-2/026-2013 and COMBIS/ LS16005, both funded by the Lower Austria Science and Education Fund (NfB).

Peer Reviewed

Postprint (published version)