Identification of unique mechanisms of nutrient acquisition in the major human fungal pathogens Candida albicans and Candida auris

The increasing number of fungal infections worldwide is a serious threat to humans. The fungus Candida albicans is usually a harmless member of the human microbiota. Under certain circumstances, it can become pathogenic and cause superficial and systemic infections. It has a remarkable metabolic flexibility and can adapt rapidly to changing environmental conditions. The emerging fungal pathogen Candida auris is multi-drug resistant to commonly used antifungal agents. Therefore, it is important to investigate the mechanisms of how both fungi metabolically adapt in the human host to discover new targets for antimycotics. A high-throughput phenotypic screening of C. auris isolates from the 4 major clades revealed common and clade/strain-specific metabolic profiles. All isolates were able to utilize a variety of di- and tripeptides as a nitrogen source. Furthermore, most C. auris isolates showed impaired growth on monocarboxylic acids as a carbon source. Genome analyses indicate that C. auris does not possess the monocarboxylate transporter Jen1 that is conserved in Candida species. Subsequent transcriptional analyses identified a significant number of induced C. auris-specific genes in response to alternative carbon sources and dipeptides. In this work a subset of uncharacterized C. albicans protein kinase deletion mutants were investigated for their role in nutrient acquisition processes. The Candida species unique protein kinase Sky2 was identified as having an important role in dipeptide and dicarboxylic acid uptake. Further, the dipeptide transporter Ptr22 and the dicarboxylate transporter Jen2 were identified as potential substrates of Sky2. Subsequent transcriptional and metabolic profiling revealed a Sky2-dependent regulation of the central metabolism and energy homeostasis in C. albicans in response to dicarboxylic acids. Taken together, this study identified unique mechanism of nutrient acquisition in the fungal pathogens C. albicans and C. auris.

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