Journal Article

Two cinnamoyl hydroxamates as potential quorum sensing inhibitors against Pseudomonas aeruginosa

Pan, Deng, Wu, Hua, Wang, Bo, Li, Jun-Jian, Jia, Ai-Qun

2024

Overview

is a ubiquitous pathogen that causes various infectious diseases through the regulation of quorum sensing (QS). The strategy of interfering with the QS systems of , coupled with a reduction in the dosage of conventional antibiotics, presents a potential solution to treating infection and mitigating antibiotic resistance. In this study, seven cinnamoyl hydroxamates were synthesized to evaluate their inhibitory effects on QS of . Among these cinnamic acid derivatives, we found cinnamoyl hydroxamic acid (CHA) and 3-methoxy-cinnamoyl hydroxamic acid (MCHA) were the two most effective candidates. Furtherly, the effect of CHA and MCHA on the production of virulence factors and biofilm of were evaluated. Ultimately, our study may offer promising potential for treating infections and reducing its virulence. The disc diffusion test were conducted to evaluate inhibitory effects on QS of seven cinnamoyl hydroxamates. The influence of CHA and MCHA on the production of virulence and flagellar motility of was furtherly explored. Scanning electron microscopy (SEM) experiment were conducted to evaluate the suppression of CHA and MCHA on the formed biofilm of . RT-qPCR was used to detect rhlI, lasA, lasB, rhlA, rhlB, and oprL genes in . docking study was performed to explore the molecular mechanism of CHA and MCHA. The synergistic effects of CHA with gentamicin were detected on biofilm cell dispersal. After treatment of CHA or MCHA, the production of multiple virulence factors, including pyocyanin, proteases, rhamnolipid, and siderophore, and swimming and swarming motilities in were inhibited significantly. And our results showed CHA and MCHA could eliminate the formed biofilm of . RT-qPCR revealed that CHA and MCHA inhibited the expression of QS related genes in . Molecular docking indicated that CHA and MCHA primarily inhibited the RhlI/R system in by competing with the cognate signaling molecule C4-HSL.Additionally, CHA exhibited potent synergistic effects with gentamicin on biofilm cell dispersal. is one of the most clinically and epidemiologically important bacteria and a primary cause of catheter-related urinary tract infections and ventilator-associated pneumonia. This study aims to explore whether cinnamoyl hydroxamates have inhibitory effects on QS. And our results indicate that CHA and MCHA, as two novel QSIs, offer promising potential for treating P. aeruginosa infections and reducing its virulence.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Acids / Anti-Bacterial Agents - chemistry / Anti-Bacterial Agents - pharmacology / Antibiotic resistance / Antibiotics / Bacteria / Bacterial Proteins - genetics / Bacterial Proteins - metabolism / Biofilms / Biofilms - drug effects / Cellular and Infection Microbiology / Cinnamates - chemistry / Cinnamates - pharmacology / Cinnamic acid / cinnamoyl hydroxamates / Epidemiology / Flagella / Gene Expression Regulation, Bacterial - drug effects / Gentamicin / Hydroxamic acid / Hydroxamic Acids - chemistry / Hydroxamic Acids - pharmacology / Infectious diseases / Microbial Sensitivity Tests / Molecular Docking Simulation / Molecular modelling / Pathogens / Pseudomonas aeruginosa / Pseudomonas aeruginosa - drug effects / Pseudomonas aeruginosa - genetics / Pyocyanin / Quantitative analysis / Quorum sensing / Quorum Sensing - drug effects / quorum sensing inhibitors / Scanning electron microscopy / Urinary tract / Ventilator-associated pneumonia / Virulence / Virulence - drug effects / Virulence factors / Virulence Factors - genetics / Virulence Factors - metabolism