title: Ribavirin suppresses bacterial virulence by targeting LysR-type transcriptional regulators.
abstract: Targeting bacterial virulence mechanisms without compromising bacterial growth is a promising strategy to prevent drug resistance. LysR-type transcriptional regulators (LTTRs) possess structural conservation across bacterial species and regulate virulence in numerous pathogens, making them attractive targets for antimicrobial agents. We targeted AphB, a Vibrio cholerae LTTR, which regulates the expression of genes encoding cholera toxin and toxin-co-regulated pilus for inhibitor designing. Since AphB ligand is unknown, we followed a molecular fragment-based approach for ligand designing using FDA-approved drugs and subsequent screen to identify molecules that exhibited high-affinity binding to AphB ligand-binding pocket. Among the identified compounds, ribavirin, an anti-viral drug, antagonized AphB functions. Ribavirin perturbed Vibrio cholerae pathogenesis in animal models. The inhibitory effects of the drug was limited to the bacteria expressing wild type AphB, but not its constitutively active mutant (AphBN100E), which represents the ligand-bound state, suggesting that ribavirin binds to the active site of AphB to exert its inhibitory role and there exists no AphB-independent mechanism of its action. Similarly, ribavirin suppressed the functions of Salmonella Typhi LTTR Hrg, indicating its broad spectrum efficacy. Moreover, ribavirin did not affect the bacterial viability in culture. This study cites an example of drug repurposing for anti-infective therapy.
authors.affiliation: Biomedical Informatics Center, National Institute of Cholera and Enteric Diseases, Kolkata, India.
authors.forename: Rahul Shubhra
authors.initials: RS
authors.lastname: Mandal
authors.affiliation: Division of Clinical Medicine, National Institute of Cholera and Enteric Diseases, Kolkata, India.
authors.forename: Atri
authors.initials: A
authors.lastname: Ta
authors.affiliation: Division of Bacteriology, National Institute of Cholera and Enteric Diseases, Kolkata, India.
authors.forename: Ritam
authors.initials: R
authors.lastname: Sinha
authors.affiliation: Division of Clinical Medicine, National Institute of Cholera and Enteric Diseases, Kolkata, India.
authors.forename: Nagaraja
authors.initials: N
authors.lastname: Theeya
authors.affiliation: Department of Biophysics, Bose Institute, Kolkata, India.
authors.forename: Anirban
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: Biomedical Informatics Center, National Institute of Cholera and Enteric Diseases, Kolkata, India.
authors.forename: Mohsina
authors.initials: M
authors.lastname: Tasneem
authors.affiliation: Department of Biophysics, Bose Institute, Kolkata, India.
authors.forename: Anirban
authors.initials: A
authors.lastname: Bhunia
authors.affiliation: Division of Bacteriology, National Institute of Cholera and Enteric Diseases, Kolkata, India.
authors.forename: Hemanta
authors.initials: H
authors.lastname: Koley
authors.affiliation: Biomedical Informatics Center, National Institute of Cholera and Enteric Diseases, Kolkata, India.|Division of Clinical Medicine, National Institute of Cholera and Enteric Diseases, Kolkata, India.
authors.forename: Santasabuj
authors.initials: S
authors.lastname: Das
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D058492:Drug Repositioning; D015964:Gene Expression Regulation, Bacterial; D008024:Ligands; D008297:Male; D051379:Mice; D008968:Molecular Conformation; D009154:Mutation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011817:Rabbits; D012254:Ribavirin / Q000494:pharmacology*; D012485:Salmonella typhi; D013379:Substrate Specificity; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014734:Vibrio cholerae / Q000235:genetics / Q000378:metabolism*; D014774:Virulence
chemical_list: C120327:AphB protein, Vibrio cholerae; D001426:Bacterial Proteins; D008024:Ligands; D015534:Trans-Activators; D014157:Transcription Factors; D012254:Ribavirin; C073470:LysR protein, Bacteria