Fragment-based screening identifies novel targets for inhibitors of conjugative transfer of antimicrobial resistance by plasmid pKM101

Scientific Reports
Bastien CasuChristian Baron

Abstract

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, we present a structure-based strategy to identify inhibitors of type IV secretion system-mediated bacterial conjugation. Using differential scanning fluorimetry we screened a fragment library and identified molecules that bind the essential TraE protein of the plasmid pKM101 conjugation machinery. Co-crystallization 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 we 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 here is generally applicable for the structure-based design of inhibitors of antimicrobial resistance gene transf...Continue Reading

References

Mar 15, 2005·Proceedings of the National Academy of Sciences of the United States of America·Laurent TerradotGabriel Waksman
Feb 17, 2006·Proceedings of the National Academy of Sciences of the United States of America·Susan BaileyPatricia C Zambryski
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Jan 23, 2016·Nature·Eric D Brown, Gerard D Wright
Sep 17, 2016·The Journal of Biological Chemistry·Bastien CasuChristian Baron

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Citations

Aug 8, 2018·FEMS Microbiology Reviews·Michelle M C BucknerLaura J V Piddock
Jun 26, 2018·Angewandte Chemie·Markus LakemeyerStephan A Sieber
Jun 24, 2019·European Journal of Oral Sciences·Aurélien FouillenAntonio Nanci
Dec 5, 2019·Journal of Enzyme Inhibition and Medicinal Chemistry·Mikhail KrasavinClaudiu T Supuran
Sep 10, 2020·Frontiers in Molecular Biosciences·Itxaso Álvarez-RodríguezItziar Alkorta
Dec 17, 2020·Molecular Microbiology·Tiago R D CostaPeter J Christie

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Methods Mentioned

BETA
NMR
electron microscopy
X-ray
thermal shift
cross-linking assay

Software Mentioned

MarvinSketch
ImageLab
AutoDockVina
Autodock Tools
LightCycler® 480
Autodock Vina
Phenix
PROCHECK
molprobity
Elbow

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