Mrr1 regulation of methylglyoxal catabolism and methylglyoxal‐induced fluconazole resistance in Candida lusitaniae

Transcription factor Mrr1, best known for its regulation of Candida azole resistance genes such as MDR1, regulates other genes that are poorly characterized. Among the other Mrr1‐regulated genes are putative methylglyoxal reductases. Methylglyoxal (MG) is a toxic metabolite that is elevated in diabetes, uremia, and sepsis, which are diseases that increase the risk for candidiasis, and MG serves as a regulatory signal in diverse organisms. Our studies in Clavispora lusitaniae, also known as Candida lusitaniae, showed that Mrr1 regulates expression of two paralogous MG reductases, MGD1 and MGD2, and that both participate in MG resistance and MG catabolism. Exogenous MG increased Mrr1‐dependent expression of MGD1 and MGD2 as well as expression of MDR1, which encodes an efflux pump that exports fluconazole. MG improved growth in the presence of fluconazole and this was largely Mrr1‐dependent with contributions from a secondary transcription factor, Cap1. Increased fluconazole resistance was also observed in mutants lacking Glo1, a Mrr1‐independent MG catabolic enzyme. Isolates from other Candida species displayed heterogeneity in MG resistance and MG stimulation of azole resistance. We propose endogenous and host‐derived MG can induce MDR1 and other Mrr1‐regulated genes causing increased drug resistance, which may contribute to some instances of fungal treatment failure. The transcription factor Mrr1 is closely associated with multidrug resistance in Candida species, but little is understood about its natural role in Candida biology. Here, we report that in Candida lusitaniae, Mrr1 regulates expression of enzymes involved in catabolism of the toxic metabolite methylglyoxal. In addition, methylglyoxal induces fluconazole resistance in a partially Mrr1‐dependent manner in C. lusitaniae.