AUTHOR=Yuan Yang , Yang Xiting , Zeng Qianglin , Li Heyue , Fu Ruyi , Du Lianming , Liu Wei , Zhang Yamei , Zhou Xikun , Chu Yiwen , Zhang Xiuyue , Zhao Kelei 

TITLE=Repurposing Dimetridazole and Ribavirin to disarm Pseudomonas aeruginosa virulence by targeting the quorum sensing system

JOURNAL=Frontiers in Microbiology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2022.978502

DOI=10.3389/fmicb.2022.978502

ISSN=1664-302X

ABSTRACT=<p><italic>Pseudomonas aeruginosa</italic> 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 <italic>P. aeruginosa</italic> reference isolate PAO1 in nutrient medium but significantly inhibited the growth of <italic>P. aeruginosa</italic> 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 <italic>P. aeruginosa</italic> quorum sensing (QS) system. The production of QS-controlled proteases, pyocyanin, and biofilm formation of <italic>P. aeruginosa</italic> PAO1 and the clinical isolates were significantly decreased by the presence of Dimetridazole or Ribavirin. Correspondingly, the majority of QS-activated genes in <italic>P. aeruginosa</italic>, including the key regulatory genes <italic>lasR</italic>, <italic>rhlR</italic>, and <italic>pqsR</italic> 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 <italic>P. aeruginosa</italic> 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 <italic>Caenorhabditis elegans</italic> and mice from <italic>P. aeruginosa</italic> infection. In conclusion, this study reports the antivirulence potentials of Dimetridazole and Ribavirin on <italic>P. aeruginosa</italic> and provides structural basis and methodological reference for the development of anti-pseudomonal drugs.</p>