Candida auris skin tropism and antifungal resistance are mediated by carbonic anhydrase Nce103

The pronounced skin tropism and pan-antifungal resistance of Candida auris pose a serious global health threat. A key question in C. auris biology is how clinical isolates acquire amphotericin B resistance. Here we demonstrate that a carbonic sensing pathway (CSP) contributes to amphotericin B resistance by modulating mitochondrial energy functions in clinical C. auris isolates. Integrated transcriptomics and proteomics identify the carbonic anhydrase Nce103 and its transcription factors Rca1 and Efg1 as important regulatory components of the CSP. The conversion of CO2 into bicarbonate sustains energy metabolism required for colonization and fitness on human skin and in nutrient-limited microenvironments. We also show that bacterial skin colonizers engage urease to release CO2 that sustains C. auris fitness and skin colonization. These findings highlight therapeutic options to re-sensitize C. auris to antifungal treatments, as well as to prevent skin colonization by blocking the CSP.