Antimicrobial peptides fight against Pseudomonas aeruginosa at a sub-inhibitory concentration via anti-QS pathway

Li Li; Jiaxin Li; Xiaodan Yu; Ruipin Cao; Meiling Hong; Zuxian Xu; Jian Ren Lu; Yinglu Wang; Hu Zhu

doi:10.1016/j.bioorg.2023.106922

Antimicrobial peptides fight against Pseudomonas aeruginosa at a sub-inhibitory concentration via anti-QS pathway

Bioorg Chem. 2023 Dec:141:106922. doi: 10.1016/j.bioorg.2023.106922. Epub 2023 Oct 17.

Authors

Li Li¹, Jiaxin Li¹, Xiaodan Yu¹, Ruipin Cao¹, Meiling Hong¹, Zuxian Xu¹, Jian Ren Lu², Yinglu Wang³, Hu Zhu⁴

Affiliations

¹ Fujian-Taiwan Science and Technology Cooperation Base of Biomedical Materials and Tissue Engineering, Engineering Research Center of Industrial Biocatalysis, Fujian Provincial Key Laboratory of Advanced Materials Oriented Chemical Engineering, College of Chemistry and Materials Science, Fujian Normal University, Fuzhou, Fujian, China.
² Biological Physics Group, Department of Physics and Astronomy, The University of Manchester, Manchester, M13 9PL, UK. Electronic address: j.lu@manchester.ac.uk.
³ Fujian-Taiwan Science and Technology Cooperation Base of Biomedical Materials and Tissue Engineering, Engineering Research Center of Industrial Biocatalysis, Fujian Provincial Key Laboratory of Advanced Materials Oriented Chemical Engineering, College of Chemistry and Materials Science, Fujian Normal University, Fuzhou, Fujian, China; State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China. Electronic address: wangyl@fjnu.edu.cn.
⁴ Fujian-Taiwan Science and Technology Cooperation Base of Biomedical Materials and Tissue Engineering, Engineering Research Center of Industrial Biocatalysis, Fujian Provincial Key Laboratory of Advanced Materials Oriented Chemical Engineering, College of Chemistry and Materials Science, Fujian Normal University, Fuzhou, Fujian, China. Electronic address: zhuhu@fjnu.edu.cn.

PMID: 37865056
DOI: 10.1016/j.bioorg.2023.106922

Abstract

The broad-spectrum antimicrobial ability of de novo designed amphiphilic antimicrobial peptides (AMPs) G(IIKK)₃I-NH₂ (G₃) and C₈-G(IIKK)₂I-NH₂ (C₈G₂) have been demonstrated. Nonetheless, their potential as anti-quorum-sensing (anti-QS) agents, particularly against the opportunistic pathogen Pseudomonas aeruginosa at subinhibitory concentrations, has received limited attention. In this study, we proved that treating P. aeruginosa PAO1 with both AMPs at subinhibitory concentrations led to significant inhibition of QS-regulated virulence factors, including pyocyanin, elastase, proteases, and bacterial motility. Additionally, the AMPs exhibited remarkable capabilities in suppressing biofilm formation and their elimination rate of mature biofilm exceeded 95%. Moreover, both AMPs substantially downregulated the expression of QS-related genes. CD analysis revealed that both AMPs induced structural alterations in the important QS-related protein LasR in vitro. Molecular docking results indicated that both peptides bind to the hydrophobic groove of the LasR dimer. Notably, upon mutating key binding sites (D5, E11, and F87) to Ala, the binding efficiency of LasR to both peptides significantly decreased. We revealed the potential of antibacterial peptides G₃ and C₈G₂ at their sub-MIC concentrations as QS inhibitors against P. aeruginosa and elucidated their action mechanism. These findings contribute to our understanding of the therapeutic potential of these peptides in combating P. aeruginosa infections by targeting the QS system.

Keywords: Anti-quorum-sensing; Antimicrobial peptides; Interaction; LasR; Pseudomonas aeruginosa.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology
Antimicrobial Peptides*
Bacterial Proteins / metabolism
Biofilms
Molecular Docking Simulation
Pseudomonas aeruginosa* / physiology
Quorum Sensing

Substances

Antimicrobial Peptides
Anti-Bacterial Agents
Bacterial Proteins