Repurposing Dimetridazole and Ribavirin to disarm virulence by targeting the quorum sensing system.

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