Transcriptional Response of Candida auris to the Mrr1 Inducers Methylglyoxal and Benomyl

ABSTRACT Candida auris is an urgent threat to human health due to its rapid spread in health care settings and its repeated development of multidrug resistance. Diseases that increase risk for C. auris infection, such as diabetes, kidney failure, or immunocompromising conditions, are associated with elevated levels of methylglyoxal (MG), a reactive dicarbonyl compound derived from several metabolic processes. In other Candida species, expression of MG reductase enzymes that catabolize and detoxify MG are controlled by Mrr1, a multidrug resistance-associated transcription factor, and MG induces Mrr1 activity. Here, we used transcriptomics and genetic assays to determine that C. auris MRR1a contributes to MG resistance, and that the main Mrr1a targets are an MG reductase and MDR1, which encodes a drug efflux protein. The C. auris Mrr1a regulon is smaller than Mrr1 regulons described in other species. In addition to MG, benomyl (BEN), a known Mrr1 stimulus, induces C. auris Mrr1 activity, and characterization of the MRR1a-dependent and -independent transcriptional responses revealed substantial overlap in genes that were differentially expressed in response to each compound. Additionally, we found that an MRR1 allele specific to one C. auris phylogenetic clade, clade III, encodes a hyperactive Mrr1 variant, and this activity correlated with higher MG resistance. C. auris MRR1a alleles were functional in Candida lusitaniae and were inducible by BEN, but not by MG, suggesting that the two Mrr1 inducers act via different mechanisms. Together, the data presented in this work contribute to the understanding of Mrr1 activity and MG resistance in C. auris. IMPORTANCE Candida auris is a fungal pathogen that has spread since its identification in 2009 and is of concern due to its high incidence of resistance against multiple classes of antifungal drugs. In other Candida species, the transcription factor Mrr1 plays a major role in resistance against azole antifungals and other toxins. More recently, Mrr1 has been recognized to contribute to resistance to methylglyoxal (MG), a toxic metabolic product that is often elevated in different disease states. MG can activate Mrr1 and its induction of Mdr1 which can protect against diverse challenges. The significance of this work lies in showing that MG is also an inducer of Mrr1 in C. auris, and that one of the major pathogenic C. auris lineages has an activating Mrr1 mutation that confers protection against MG.