Chemical inhibition of histidine biosynthesis curtails M. tuberculosis infection

Abstract

To overcome the drug resistance crisis and shorten the current duration of human tuberculosis (TB) therapy, new anti-TB molecules is required. In an earlier study, we have shown that Mycobacterium tuberculosis (Mtb), the causative agent of TB, with a fractured de novo histidine biosynthesis fails to mount TB infection in mouse model, emboldening that disrupting the function of this pathway may constitute a novel strategy to curtailing TB infection. In this study, through a target based approach we have designed a number of triazole scaffold molecules specific to imidazole glycerol phosphate dehydratase (IGPD; HisB) of this pathway and have delineated atomic level interactions between the enzyme and inhibitors which pinpointed the specificity and the inhibitory mechanism. Importantly, these molecules exhibited significant potency against free as well as macrophage-internalized wild-type and drug-resistant clinical isolates in culture medium. Notably, a couple of these compounds showed efficacy in reducing the bacterial burden in Mtb-infected mouse model. The chemical inhibition of IGPD induces histidine auxotrophy in Mtb and brings in new prospects to the area of anti-TB drug discovery.