Institut für Molekulare Infektionsbiologie, Universität Würzburg, Würzburg, Germany.
Department of Clinical Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
Antimicrob Agents Chemother. 2018 Nov 26;62(12). doi: 10.1128/AAC.01655-18. Print 2018 Dec.
Gain-of-function mutations in the zinc cluster transcription factors Mrr1, Tac1, and Upc2, which result in constitutive overexpression of their target genes, are a frequent cause of fluconazole resistance in the pathogenic yeast In this study, we show that an activated form of another zinc cluster transcription factor, Stb5, confers resistance to the natural compound beauvericin via the overexpression of , encoding an efflux pump of the ATP-binding cassette transporter superfamily. Beauvericin was recently shown to potentiate the activity of azole drugs against Although Yor1 did not contribute to fluconazole resistance when cells were treated with the drug alone, Stb5-mediated overexpression diminished the synergistic effect of the fluconazole-beauvericin combination, thereby enhancing fluconazole resistance in beauvericin-treated cells. Stb5-mediated overexpression also suppressed the inhibition of hyphal growth, an important virulence trait of , by beauvericin. Therefore, activating mutations in Stb5, which result in constitutive overexpression, may enable to acquire resistance to beauvericin and thereby overcome both the sensitization to azole drugs and the inhibition of morphogenesis caused by this compound.
锌指转录因子 Mrr1、Tac1 和 Upc2 的功能获得性突变导致其靶基因的组成性过表达，是致病性酵母中氟康唑耐药的常见原因。在这项研究中，我们表明，另一种锌指转录因子 Stb5 的激活形式通过过度表达编码 ABC 转运蛋白超家族外排泵的 ，赋予了对天然化合物 beauvericin 的抗性。beauvericin 最近被证明可以增强唑类药物对 的活性。尽管在单独用氟康唑处理 细胞时，Yor1 并没有导致氟康唑耐药，但 Stb5 介导的 过表达降低了氟康唑-beauvericin 组合的协同作用，从而增强了 beauvericin 处理的 细胞对氟康唑的耐药性。Stb5 介导的 过表达也抑制了 beauvericin 对 的菌丝生长（一种重要的毒力特征）的抑制。因此，Stb5 的激活突变导致组成性过表达，可能使 获得对 beauvericin 的耐药性，从而克服该化合物引起的对唑类药物的敏感性和形态发生的抑制。
