Journal article

The Inosine Monophosphate Dehydrogenase, GuaB2, Is a Vulnerable New Bactericidal Drug Target for Tuberculosis

Vinayak Singh, Stefano Donini, Angela Pacitto, Claudia Sala, Ruben C Hartkoorn, Neeraj Dhar, Gyorgy Keri, David B Ascher, Guillaume Mondesert, Anthony Vocat, Andreanne Lupien, Raphael Sommer, Helene Vermet, Sophie Lagrane, Joe Buechler, Digby F Warner, John D McKinney, Janos Pato, Stewart T Cole, Tom L Blundell Show all

ACS INFECTIOUS DISEASES | AMER CHEMICAL SOC | Published : 2017

Abstract

VCC234718, a molecule with growth inhibitory activity against Mycobacterium tuberculosis (Mtb), was identified by phenotypic screening of a 15344-compound library. Sequencing of a VCC234718-resistant mutant identified a Y487C substitution in the inosine monophosphate dehydrogenase, GuaB2, which was subsequently validated to be the primary molecular target of VCC234718 in Mtb. VCC234718 inhibits Mtb GuaB2 with a Ki of 100 nM and is uncompetitive with respect to IMP and NAD+. This compound binds at the NAD+ site, after IMP has bound, and makes direct interactions with IMP; therefore, the inhibitor is by definition uncompetitive. VCC234718 forms strong pi interactions with the Y487 residue side..

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University of Melbourne Researchers

Grants

Awarded by European Community


Awarded by Senior International Research Scholar's grant from the HHMI


Awarded by Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG)


Awarded by NHMRC CJ Martin Fellowship


Awarded by Swiss National Science Foundation


Awarded by Medical Research Council


Funding Acknowledgements

This work was funded by the European Community's Seventh Framework Programme (Grant 260872); the South African Medical Research Council (to V.M.); the National Research Foundation of South Africa (to V.M.); a Senior International Research Scholar's grant from the HHMI (Grant 55007649 to V.M.); the Bill and Melinda Gates Foundation (to A.P. and T.L.B.), a Newton Fund RCUK-CONFAP grant awarded by The Medical Research Council (MRC) and Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG) (Grant MR/M026302/1 to T.L.B. and D.B.A.), a NHMRC CJ Martin Fellowship (Grant APP1072476 to D.B.A.); the Swiss National Science Foundation (31003A-162641) and the Fondation Beytout (to S.T.C.); the University of Cambridge and The Wellcome Trust for facilities and support (to T.L.B.).