Maura Damien, Hazan Ronen, Kitao Tomoe, Ballok Alicia E, Rahme Laurence G
Department of Surgery, Massachusetts General Hospital, Boston MA 02114, USA.
Department of Microbiology and Immunobiology, Harvard Medical School, Boston MA 02115, USA.
Sci Rep. 2016 Sep 28;6:34083. doi: 10.1038/srep34083.
Pseudomonas aeruginosa defies eradication by antibiotics and is responsible for acute and chronic human infections due to a wide variety of virulence factors. Currently, it is believed that MvfR (PqsR) controls the expression of many of these factors indirectly via the pqs and phnAB operons. Here we provide strong evidence that MvfR may also bind and directly regulate the expression of additional 35 loci across the P. aeruginosa genome, including major regulators and virulence factors, such as the quorum sensing (QS) regulators lasR and rhlR, and genes involved in protein secretion, translation, and response to oxidative stress. We show that these anti-oxidant systems, AhpC-F, AhpB-TrxB2 and Dps, are critical for P. aeruginosa survival to reactive oxygen species and antibiotic tolerance. Considering that MvfR regulated compounds generate reactive oxygen species, this indicates a tightly regulated QS self-defense anti-poisoning system. These findings also challenge the current hierarchical regulation model of P. aeruginosa QS systems by revealing new interconnections between them that suggest a circular model. Moreover, they uncover a novel role for MvfR in self-defense that favors antibiotic tolerance and cell survival, further demonstrating MvfR as a highly desirable anti-virulence target.
铜绿假单胞菌难以被抗生素根除，因其具有多种毒力因子，可引发人类急慢性感染。目前认为，MvfR（PqsR）通过pqs和phnAB操纵子间接控制许多此类因子的表达。在此，我们提供了有力证据，表明MvfR可能还会结合并直接调控铜绿假单胞菌基因组中另外35个位点的表达，这些位点包括主要调控因子和毒力因子，如群体感应（QS）调控因子lasR和rhlR，以及参与蛋白质分泌、翻译和氧化应激反应的基因。我们发现，这些抗氧化系统AhpC-F、AhpB-TrxB2和Dps对于铜绿假单胞菌抵抗活性氧和抗生素耐受性至关重要。鉴于MvfR调控的化合物会产生活性氧，这表明存在一个严格调控的QS自我防御抗中毒系统。这些发现还通过揭示铜绿假单胞菌QS系统之间新的相互联系，对当前的层级调控模型提出了挑战，提示了一个循环模型。此外，它们揭示了MvfR在自我防御中的新作用，这种作用有利于抗生素耐受性和细胞存活，进一步证明MvfR是一个极具吸引力的抗毒力靶点。
