I had the pleasure to host Dr, Baron Christian, Professor in the Department of Biochemistry and Molecular Medicine in the Faculty of Medicine at U de Montréal. Dr. Baron leads a team of researchers that set out to understand the process by which antibiotic resistance genes actually spread; and identify a way to block the transfer of resistance genes. They published an article in Scientific Reports and we wanted to share the findings of that article with you.
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Until next time!
Chiraz Guessaier, CDA Oasis Manager
The increasing frequency of antimicrobial resistance is a problem of global importance. Novel strategies are urgently needed to understand and inhibit antimicrobial resistance gene transmission that is mechanistically related to bacterial virulence functions.
The conjugative transfer of plasmids by type IV secretion systems is a major contributor to antimicrobial resistance gene transfer. Here, the authors present a structure-based strategy to identify inhibitors of type IV secretion system-mediated bacterial conjugation.
Using differential scanning fluorimetry, the authors screened a fragment library and identified molecules that bind the essential TraE protein of the plasmid pKM101 conjugation machinery. Cocrystallization revealed that fragments bind two alternative sites of the protein and one of them is a novel inhibitor binding site.
Based on the structural information on fragment binding, the authors designed novel small molecules that have improved binding affinity. These molecules inhibit the dimerization of TraE, bind to both inhibitor binding sites on TraE and inhibit the conjugative transfer of plasmid pKM101.
The strategy presented in the article is generally applicable for the structure-based design of inhibitors of antimicrobial resistance gene transfer and of bacterial virulence.
Full Interview (5.07″)