Population genomics reveals environmental reservoirs and antifungal resistance mechanisms in major non-albicans Candida species

Non-albicans Candida (NAC) species are associated with increasing antifungal resistance, yet the contribution of the environmental niche to epidemiological transmission and the development of antifungal resistance remains unclear. In this study, we isolated environmental strains of three major NAC species: Candida tropicalis, Candida glabrata , and Candida parapsilosis sensu stricto. Population genomic studies were conducted on 1743 NAC strains by integrating environmental isolates with publicly available sequences of clinical isolates. Population structure analyses revealed genetic connectivity between environmental and clinical reservoirs for all three species. These findings support the hypothesis that environmental and clinical NAC populations are interconnected through human commensal dissemination or bidirectional exchange. Although environmental isolates exhibited lower resistance rates, azole resistance of environmental subpopulations was generally higher than echinocandin resistance, especially in C. tropicalis . This pattern is consistent with the possibility that environmental azole exposure may contribute to resistance selection, while direct causal evidence remains to be established. Furthermore, genome-wide association studies provided a dataset of candidate resistance-associated genes for major clinical azoles and echinocandins. The genes related to cell adhesion and major facilitator superfamily transporters were frequently detected. The dataset provides a foundation for further experimental validation work to identify potential novel resistance mechanisms. Through the environmental reservoir of NAC isolates, our findings provide genomic evidence under One Health framework on antifungal resistance, highlighting the need for environmental fungal pathogen surveillance and fungicide stewardship to protect public health.