Journal article
The inosine monophosphate dehydrogenase, GuaB2, is a vulnerable new bactericidal drug target for tuberculosis
V Singh, S Donini, A Pacitto, C Sala, RC Hartkoorn, N Dhar, G Keri, DB Ascher, G Mondésert, A Vocat, A Lupien, R Sommer, H Vermet, S Lagrange, J Buechler, DF Warner, JD McKinney, J Pato, ST Cole, TL 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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Awarded by South African 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.).