Parallel evolution under constraint shapes echinocandin resistance in Candida auris

Candida auris, a globally spreading fungal pathogen, frequently develops drug resistance during outbreaks, yet the factors influencing its emergence and maintenance remain unclear. Our study examined the evolutionary forces driving echinocandin resistance in C. auris, a predominantly clonal pathogen. By analyzing over 600 genomes, we identified mutations in the {beta}-1,3-glucan synthase gene FKS1 as the primary factor responsible for resistance to an echinocandin drug.

Tracing the ancestry of this population, we discovered that shared resistance mutations often clustered in small groups, typically comprising 2-3 closely related isolates. However, some clusters could contain up to 16 isolates. This pattern suggests that these resistant clusters typically originated from local transmissions, with nearly all resistant clusters collected in the same year and region.

To further investigate population-level selection, we assessed adaptive signatures in FKS1 and its highly divergent paralog FKS2 across 22,000 genomes. Our findings revealed an abundance of nonsynonymous polymorphisms in FKS1, mainly due to independent and recurrent mutations at specific resistance hotspots. This indicates parallel evolution and incomplete fixation of adaptive alleles. In contrast, FKS2 displayed no evidence of hotspots and little support for diversifying selection.

In summary, our results suggest that resistance mutations arise under strong genetic constraint, with adaptation predominantly limited to one FKS homolog and primarily occurring at mutational hotspots.