Micafungin microevolution in Candida auris reveals resistance development without in vivo fitness compromise

Candida auris is an emerging multidrug-resistant pathogen with high transmissibility in healthcare settings. Although echinocandin resistance in Candida is typically associated with fitness loss, we found that micafungin-resistant C. auris strains (MICA^evo) generated from two distinct source isolates (AR0381 and AR0387) via experimental microevolution retained full virulence. Evolved strains developed stable resistance to multiple echinocandins, while AR0387 (B8441), originating from MICA^evo strain, also acquired increased azole tolerance. Whole-genome sequencing revealed clinically relevant mutations in FKS1, as well as changes in genes involved in ergosterol biosynthesis (ERG3), amino acid metabolism, and PKA signaling. Despite in vitro sensitivity to cell wall stressors, resistant strains maintained or even enhanced colonization in a murine systemic infection model. Independently evolved strains showed similar antifungal resistance profiles, and although minor differences of pathogenic potential were noted, no consistent virulence attenuation was observed, indicating the reproducibility of phenotype changes. These findings suggest that C. auris can acquire echinocandin resistance without compromising pathogenicity, supporting its persistence and spread in clinical settings.