Institute of Biology-Microbiology, Freie Universität Berlin, Berlin, Germany.
Center for Biotechnology, Bielefeld University, Bielefeld, Germany.
Antioxid Redox Signal. 2019 Dec 1;31(16):1235-1252. doi: 10.1089/ars.2019.7750. Epub 2019 Aug 9.
Quinone compounds are electron carriers and have antimicrobial and toxic properties due to their mode of actions as electrophiles and oxidants. However, the regulatory mechanism of quinone resistance is less well understood in the pathogen . Methylhydroquinone (MHQ) caused a thiol-specific oxidative and electrophile stress response in the transcriptome as revealed by the induction of the PerR, QsrR, CstR, CtsR, and HrcA regulons. The operon was most strongly upregulated by MHQ and was renamed as operon based on its homology to the locus. Here, we characterized the MarR-type regulator MhqR (SACOL2531) as quinone-sensing repressor of the operon, which confers quinone and antimicrobial resistance in . The operon responds specifically to MHQ and less pronounced to pyocyanin and ciprofloxacin, but not to reactive oxygen species (ROS), hypochlorous acid, or aldehydes. The MhqR repressor binds specifically to a 9-9 bp inverted repeat (MhqR operator) upstream of the operon and is inactivated by MHQ , which does not involve a thiol-based mechanism. In phenotypic assays, the deletion mutant was resistant to MHQ and quinone-like antimicrobial compounds, including pyocyanin, ciprofloxacin, norfloxacin, and rifampicin. In addition, the mutant was sensitive to sublethal ROS and 24 h post-macrophage infections but acquired an improved survival under lethal ROS stress and after long-term infections. Our results provide a link between quinone and antimicrobial resistance the MhqR regulon of . The MhqR regulon was identified as a novel resistance mechanism towards quinone-like antimicrobials and contributes to virulence of under long-term infections.
醌类化合物是电子载体，由于其作为亲电体和氧化剂的作用方式，具有抗菌和毒性。然而，病原体中醌类耐药的调节机制了解较少。甲基氢醌（MHQ）在转录组中引起硫醇特异性氧化和亲电应激反应，如 PerR、QsrR、CstR、CtsR 和 HrcA 调控子的诱导所揭示的那样。该 操纵子受 MHQ 强烈诱导，并根据其与 基因座的同源性更名为 操纵子。在这里，我们将 MarR 型调节剂 MhqR（SACOL2531）表征为 操纵子的醌感应抑制剂，该抑制剂赋予 对醌类和抗菌剂的抗性。 操纵子特异性响应 MHQ，对绿脓菌素和环丙沙星的响应程度较低，但对活性氧（ROS）、次氯酸或醛不响应。MhqR 抑制剂特异性结合 操纵子上游的 9-9 bp 反向重复（MhqR 操纵子），并被 MHQ 失活，这与基于硫醇的机制无关。在表型测定中， 缺失突变体对 MHQ 和醌类抗菌化合物（包括绿脓菌素、环丙沙星、诺氟沙星和利福平）具有抗性。此外， 突变体对亚致死 ROS 和巨噬细胞感染后 24 小时敏感，但在致死 ROS 应激和长期感染后获得更好的生存能力。我们的结果提供了醌类和抗菌抗性之间的联系 为 的 MhqR 调控子。MhqR 调控子被确定为一种新型的醌类类似物抗菌耐药机制，并有助于 在长期感染下的毒力。
