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

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.

Discovery of New Fusobacterium nucleatum Inhibitors to Attenuate Migratory Capability of Colon Cancer Cells by the Drug Repositioning Strategy

“…Recent studies showed these compounds inhibited the growth of Clostridium difficile in vitro . In addition, dimetridazole was found to decrease Pseudomonas aeruginosa virulence by targeting the quorum sensing system . Furazolidone has been used in the treatment of certain bacterial and protozoan infections in human and animals for more than 60 years. , It displayed potent antiproliferative properties in a series of acute myeloid leukemia (AML) cells by inhibiting leukemia fusion proteins …”

Fabrication and evaluation of ribavirin-loaded electrospun nanofibers as an antimicrobial wound dressing

“…In a recent study by Yuan et al , a combination of dimetridazole and ribavirin had no significant effect on the growth of P. aeruginosa PAO1 at concentrations lower than 244.2 μg/mL ( Yuan et al, 2022 ). These results suggest that dimetridazole and ribavirin at routinely used concentrations had poor antibacterial activity against P. aeruginosa PAO1 but might inhibit the quorum sensing (QS) system.…”

“…One of the medications explored for their antimicrobial activity is ribavirin. It has been reported that ribavirin successfully protected Caenorhabditis elegans and mice from P. aeruginosa infection ( Yuan et al, 2022 ). Ribavirin, an early-stage antiviral drug, has unique antimicrobial activities, especially against P. aeruginosa and Candida albicans ( C. albicans ).…”

“…The mechanism by which ribavirin acts as an antimicrobial drug varies according to the type of its targeted microbe. Unlike conventional antibiotics, which are associated with the risk of antibiotic resistance, they act by perturbing the bacterial virulence system without killing or stopping their growth, rendering the pathogens disarmed, which might be a promising mechanism to prevent drug resistance ( Mandal et al, 2016 , Yuan et al, 2022 ). Hence, this antiviral drug is a promising agent that can be fabricated and repurposed as anti-pseudomonal drugs.…”

Antiviral İlaçlarin Hastane Enfeksiyon Etkeni Pseudomonas Aeruginosa Üzerinde Sinerjistik Etkisinin Araştirilmasi

“…aeruginosa, farklı yerlerden izole edilebilen ve klinikte önemli bir enfeksiyon kaynağı olan Gram negatif fırsatçı bir patojen bakteridir [29,30]. Genom yapısı ve hücre iletişim mekanizması [quarum sensing-QS], virülans ve direncin gelişmesinde etkili bir özellik olarak kabul edilmiştir [31,32].…”