Agricultural azole fungicides induce cross-resistance to medical antifungals in Candida tropicalis: a One Health perspective on antifungal resistance

The human opportunistic fungal pathogen Candida tropicalis is widely distributed in natural environments. In recent decades, the prevalence of azole-resistant isolates has increased markedly in the Asia-Pacific and Latin America. This epidemiological change could be associated with the extensive application of azole fungicides in modern agriculture. In this study, we demonstrate that exposure to four widely used agricultural azoles (difenoconazole, diniconazole, flutriafol, and hexaconazole) induces cross-resistance to medical azoles in an initially susceptible C. tropicalis strain. The evolved azole-resistant strains exhibited altered cellular and colony morphologies, along with changes in growth rates. Genomic analyses revealed that all evolved strains were aneuploid, with either partial chromosomal segment amplifications or extra chromosomes. Global transcriptomic analysis showed that many azole resistance-associated genes located within these amplified regions were upregulated, potentially contributing to resistance against both clinical and agricultural azoles. These findings highlight the potential role of agricultural azoles as the environmental drivers of antifungal resistance in the medically important fungal pathogen C. tropicalis, underscoring the importance of a One Health approach to antifungal stewardship.