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 () and Luyan Z. Ma ()
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Zhaoxiao Yu: Chinese Academy of Sciences
Zhikun Wu: Wuhan University
Dejian Liu: Chinese Academy of Sciences
Haoyu Liu: Southern University of Science and Technology
Yu Zhang: Chinese Academy of Sciences
Yaqian Zheng: Chinese Academy of Sciences
Yanhong Huang: Southern University of Science and Technology
Shumin Liao: Southern University of Science and Technology
Yu Wei: Wuhan University
Wei Huang: Wuhan University
Zhenyu Zhang: Chinese Academy of Sciences
Xi Liu: Chinese Academy of Sciences
Haiying Yu: Chinese Academy of Sciences
Di Wang: Chinese Academy of Sciences
Liang Li: Southern University of Science and Technology
Feng Long: Wuhan University
Luyan Z. Ma: Chinese Academy of Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57294-8

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