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Repurposing Dimetridazole and Ribavirin to disarm Pseudomonas aeruginosa virulence by targeting the quorum sensing
Yang Yuan1,2, Xiting Yang2, Qianglin Zeng2
1Key Laboratory of Bio-resources and Eco-environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, Sichuan, China.
Abstract:
Pseudomonas aeruginosa relies on its complex cellular regulatory network to produce a series of virulence factors and to cause various acute and chronic infections in a wide range of hosts. Compared with traditional antibiotics which frequently accompany with widespread antibiotic resistance, crippling the virulence system of bacteria is expected to be a promising anti-infective strategy. In this study, Dimetridazole and Ribavirin, which had poor antibacterial activities on P. aeruginosa reference isolate PAO1 in nutrient medium but significantly inhibited the growth of P. aeruginosa PAO1 in M9-adenosine, were selected from 40 marketed compounds with similar core structure (furan, benzofuran, or flavonoids) to the acyl-homoserine lactone signals of P. aeruginosa quorum sensing (QS) system. The production of QS-controlled proteases, pyocyanin, and biofilm formation of P. aeruginosa PAO1 and the clinical isolates were significantly decreased by the presence of Dimetridazole or Ribavirin. Correspondingly, the majority of QS-activated genes in P. aeruginosa, including the key regulatory genes lasR, rhlR, and pqsR and their downstream genes, were significantly inhibited by Ribavirin or Dimetridazole, as determined by RNA-sequencing and quantitative PCR. Furthermore, the susceptibilities of drug-resistant P. aeruginosa isolates to polymyxin B, meropenem, and kanamycin were remarkably promoted by the synergistic application of Dimetridazole or Ribavirin. Finally, the treatment of Ribavirin or Dimetridazole effectively protected Caenorhabditis elegans and mice from P. aeruginosa infection. In conclusion, this study reports the antivirulence potentials of Dimetridazole and Ribavirin on P. aeruginosa and provides structural basis and methodological reference for the development of anti-pseudomonal drugs.
Insights
Dimetridazole and Ribavirin effectively inhibit Pseudomonas aeruginosa virulence by targeting quorum sensing (QS) pathways, reducing infection in animal models and restoring antibiotic susceptibility in resistant strains.
Area of Science:
- Microbiology
- Infectious Diseases
- Drug Discovery
Background:
- Pseudomonas aeruginosa infections are challenging due to complex regulatory networks and virulence factors.
- Traditional antibiotics face widespread resistance, necessitating novel anti-infective strategies like virulence inhibition.
- Quorum sensing (QS) is a key regulatory system controlling P. aeruginosa virulence.
Purpose of the Study:
- To identify compounds that inhibit P. aeruginosa virulence by targeting its QS system.
- To evaluate the antivirulence potential of Dimetridazole and Ribavirin against P. aeruginosa.
- To assess the synergistic effects of these compounds with existing antibiotics.
Main Methods:
- Screening of 40 marketed compounds for P. aeruginosa growth inhibition in M9-adenosine medium.
- Assessing the impact of Dimetridazole and Ribavirin on QS-controlled virulence factors (proteases, pyocyanin, biofilm).
- RNA-sequencing and quantitative PCR to analyze gene expression changes.
- Evaluating synergistic effects with antibiotics and in vivo efficacy in Caenorhabditis elegans and mice models.
Main Results:
- Dimetridazole and Ribavirin significantly inhibited P. aeruginosa QS, virulence factor production, and biofilm formation.
- These compounds suppressed key QS regulatory genes (lasR, rhlR, pqsR) and their downstream targets.
- Synergistic application with Dimetridazole or Ribavirin restored susceptibility of resistant P. aeruginosa to polymyxin B, meropenem, and kanamycin.
- Treatment with Ribavirin or Dimetridazole effectively protected against P. aeruginosa infection in C. elegans and mice.
Conclusions:
- Dimetridazole and Ribavirin exhibit significant antivirulence potential against Pseudomonas aeruginosa by targeting QS pathways.
- These compounds offer a promising strategy for developing novel anti-pseudomonal drugs, potentially overcoming antibiotic resistance.
- The study provides a structural basis and methodological reference for future antivirulence drug development.
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