Essential but Not Vulnerable: Indazole Sulfonamides Targeting Inosine Monophosphate Dehydrogenase as Potential Leads against Mycobacterium tuberculosis
Yumi Park, Angela Pacitto, Tracy Bayliss, Laura AT Cleghorn, Zhe Wang, Travis Hartman, Kriti Arora, Thomas R Ioerger, Jim Sacchettini, Menico Rizzi, Stefano Donini, Tom L Blundell, David B Ascher, Kyu Rhee, Ardala Breda, Nian Zhou, Veronique Dartois, Surendranadha Reddy Jonnala, Laura E Via, Valerie Mizrahi Show all
ACS Infectious Diseases | AMER CHEMICAL SOC | Published : 2017
A potent, noncytotoxic indazole sulfonamide was identified by high-throughput screening of >100,000 synthetic compounds for activity against Mycobacterium tuberculosis (Mtb). This noncytotoxic compound did not directly inhibit cell wall biogenesis but triggered a slow lysis of Mtb cells as measured by release of intracellular green fluorescent protein (GFP). Isolation of resistant mutants followed by whole-genome sequencing showed an unusual gene amplification of a 40 gene region spanning from Rv3371 to Rv3411c and in one case a potential promoter mutation upstream of guaB2 (Rv3411c) encoding inosine monophosphate dehydrogenase (IMPDH). Subsequent biochemical validation confirmed direct inhi..View full abstract
Awarded by NHMRC
Awarded by Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG)
Awarded by NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
This work was funded, in part, by the Intramural Research Program of NIAID and in part by grants from the Foundation for the National Institutes of Health with support from the Bill & Melinda Gates Foundation (to C.E.B. III, V.M., and P.W.), and the South African Medical Research Council (to V.M.). D.B.A. was supported by an NHMRC C. J. Martin Fellowship (APP1072476). D.B.A. and T.L.B received funding from the Newton Fund RCUK-CONFAP Grant awarded by The Medical Research Council (MRC) and Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG) (MR/M026302/1). P.W. received joint funding from the Bill and Melinda Gates Foundation and Wellcome Trust for A Centre of Excellence for Lead Optimisation for Diseases of the Developing World. We acknowledge Beth Fischer and Vinod Nair for help with electron microscopy.