Ribavirin suppresses bacterial virulence by targeting LysR-type transcriptional regulators

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 attractiv...

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Published in:Scientific reports 2016-12, Vol.6 (1), p.39454-39454, Article 39454
Main Authors: Mandal, Rahul Shubhra, Ta, Atri, Sinha, Ritam, Theeya, Nagaraja, Ghosh, Anirban, Tasneem, Mohsina, Bhunia, Anirban, Koley, Hemanta, Das, Santasabuj
Format: Article
Language:English
Subjects:
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Animal models
Antimicrobial agents
Antiviral agents
Bacteria
Cholera toxin
Drug resistance
Humanities and Social Sciences
Ligands
multidisciplinary
Pathogens
Ribavirin
Science
Toxins
Transcription
Virulence
Waterborne diseases
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Summary: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 (AphB N100E ), 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.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep39454