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.

中文翻译：

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Mrr1 调节甲基乙二醛分解代谢和甲基乙二醛诱导的念珠菌对氟康唑的耐药性

转录因子 Mrr1 以其对念珠菌唑抗性基因（如MDR1）的调节而闻名，它调节其他特征不佳的基因。其他受 Mrr1 调节的基因是假定的甲基乙二醛还原酶。甲基乙二醛 (MG) 是一种有毒代谢物，在糖尿病、尿毒症和败血症中升高，这些疾病会增加念珠菌病的风险，而 MG 在多种生物体中充当调节信号。我们对Clavispora lusitaniae（也称为Candida lusitaniae）的研究表明，Mrr1 调节两种旁系同源 MG 还原酶MGD1和MGD2 的表达，并且都参与 MG 抵抗和 MG 分解代谢。外源性 MG 增加了MGD1和MGD2的Mrr1依赖性表达以及MDR1 的表达，MDR1编码输出氟康唑的外排泵。在氟康唑存在的情况下，MG 改善了生长，这在很大程度上是 Mrr1 依赖性的，来自次级转录因子 Cap1 的贡献。在缺乏 Glo1（一种独立于 Mrr1 的 MG 分解代谢酶）的突变体中也观察到氟康唑耐药性增加。来自其他念珠菌属的分离株在 MG 抗性和 MG 对唑类抗性的刺激方面表现出异质性。我们提出内源性和宿主来源的 MG 可以诱导MDR1 和其他 Mrr1 调节的基因导致耐药性增加，这可能导致某些真菌治疗失败。