Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.
Department of Medical Education, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
Antimicrob Agents Chemother. 2018 Oct 24;62(11). doi: 10.1128/AAC.00968-18. Print 2018 Nov.
Farnesol, a quorum-sensing molecule, inhibits hyphal formation, affects its biofilm formation and dispersal, and impacts its stress response. Several aspects of farnesol's mechanism of action remain incompletely uncharacterized. Among these are a thorough accounting of the cellular receptors and transporters for farnesol. This work suggests these processes are linked through the Zn cluster transcription factors Tac1 and Znc1 and their induction of the multidrug efflux pump Cdr1. Specifically, we have demonstrated that Tac1 and Znc1 are functionally activated by farnesol through a mechanism that mimics other means of hyperactivation of Zn cluster transcription factors. This is consistent with our observation that many genes acutely induced by farnesol are dependent on , , or both. A related molecule, 1-dodecanol, invokes a similar response, while several other proposed quorum-sensing molecules do not. Tac1 and Znc1 both bind to and upregulate the promoter in response to farnesol. Differences in inducer and DNA binding specificity lead to Tac1 and Znc1 having overlapping, but nonidentical, regulons. Induction of genes by farnesol via Tac1 and Znc1 was inversely related to the level of present in the cell, suggesting a model in which induction of by Tac1 and Znc1 leads to an increase in farnesol efflux. Consistent with this premise, our results show that expression, and its regulation by and , facilitates growth in the presence of high farnesol concentrations in and in certain strains of its close relative, .
法呢醇是一种群体感应分子，可抑制菌丝形成，影响其生物膜形成和分散，并影响其应激反应。法呢醇的作用机制仍有几个方面尚未完全阐明。其中包括对法呢醇的细胞受体和转运蛋白进行全面描述。这项工作表明，这些过程通过 Zn 簇转录因子 Tac1 和 Znc1 及其对多药外排泵 Cdr1 的诱导联系在一起。具体而言，我们已经证明，法呢醇通过一种模拟 Zn 簇转录因子过度激活的其他机制来功能性地激活 Tac1 和 Znc1。这与我们的观察结果一致，即法呢醇急性诱导的许多基因依赖于 Tac1、Znc1 或两者。一种相关的分子，1-十二醇，引起类似的反应，而其他几种被提议的群体感应分子则没有。Tac1 和 Znc1 都结合并上调响应法呢醇的 启动子。诱导剂和 DNA 结合特异性的差异导致 Tac1 和 Znc1 具有重叠但非完全相同的调控区。法呢醇通过 Tac1 和 Znc1 诱导基因的表达与细胞中存在的 水平呈负相关，这表明 Tac1 和 Znc1 通过诱导 来增加法呢醇外排的模型。与这一前提一致，我们的结果表明， 表达及其受 Tac1 和 Znc1 的调节，有助于在高浓度法呢醇存在下在 和其近亲的某些菌株中生长。
