Dual-function regulator MexL as a target to control phenazines production and pathogenesis of Pseudomonas aeruginosa
Zhaoxiao Yu, Zhikun Wu, Dejian Liu, Haoyu Liu, Yu Zhang, Yaqian Zheng, Yanhong Huang, Shumin Liao, Yu Wei, Wei Huang, Zhenyu Zhang, Xi Liu, Haiying Yu, Di Wang, Liang Li, Feng Long, Z. Luyan
Abstract
Antibiotic resistance or tolerance of pathogens has become one of the global public crises. Finding new drug targets may open up a way of infection control. Phenazine pyocyanin (PYO) is an important virulence factor produced by the pathogen Pseudomonas aeruginosa. Here we show that a multidrug efflux pump repressor, MexL, acts as a transcriptional activator to enhance phenazines production via binding with a conserved DNA motif within the promoters of phenazines biosynthesis genes. Moreover, PYO functions as a self-regulating ligand of MexL for restricting its own production and the mexL knockout attenuates the virulence and antibiotics tolerance of P. aeruginosa. Based on the structure of MexL we resolve, we find two antimicrobials that can interact with MexL to reduce the PYO production and virulence of P. aeruginosa. Our in vivo studies suggest that the antimicrobials combination by using MexL-antagonists to reduce bacterial virulence and enhance the efficacy of common antibiotics can be an effective way to combat P. aeruginosa infection. Finding new drug targets may open up a way to combat microbial infections. In this work, authors present the molecular basis for the dual-function regulator MexL as a target to control the virulence and pathogenesis of opportunistic pathogen Pseudomonas aeruginosa.