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

ACS infectious diseases, Volume: 3, Issue: 1
January 13, 2017
Vinayak Singh V, Stefano Donini S, Angela Pacitto A, Claudia Sala C, Ruben C Hartkoorn RC, Neeraj Dhar N, Gyorgy Keri G, David B Ascher DB, Guillaume Mondésert G, Anthony Vocat A, Andréanne Lupien A, Raphael Sommer R, Hélène Vermet H, Sophie Lagrange S, Joe Buechler J, Digby F Warner DF, John D McKinney JD, Janos Pato J, Stewart T Cole ST, Tom L Blundell TL, Menico Rizzi M, Valerie Mizrahi V

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 K 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 chain from the adjacent protomer in the tetramer, explaining the resistance-conferring mutation. In addition to sensitizing Mtb to VCC234718, depletion of GuaB2 was bactericidal in Mtb in vitro and in macrophages. When supplied at a high concentration (≥125 μM), guanine alleviated the toxicity of VCC234718 treatment or GuaB2 depletion via purine salvage. However, transcriptional silencing of guaB2 prevented Mtb from establishing an infection in mice, confirming that Mtb has limited access to guanine in this animal model. Together, these data provide compelling validation of GuaB2 as a new tuberculosis drug target.

Courtesy of the U.S. National Library of Medicine