Disruption of De Novo Histidine Biosynthesis of <i>Mycobacterium tuberculosis</i> Affects the Depletion of the Pathogen

Mycobacterium tuberculosis ( Mtb ), the causative agent of human tuberculosis (TB), employs its de novo histidine (His) biosynthesis to escape host-inflicted His starvation. This makes the enzymes involved in this biosynthetic pathway promising anti-TB drug targets. In this study, employing the high-resolution crystal structure of imidazole glycerol phosphate dehydratase (IGPD) of the Mtb His pathway, three triazole scaffold molecules were identified as potential inhibitors of this enzyme. These high-resolution crystal structures of the enzyme-inhibitor complexes elucidated the key interactions responsible for their binding specificity and affinity. We also studied the interactions of these inhibitors with the enzyme at the atomic level and tested their cytotoxicity and efficacy in in vitro and in vivo models. Our findings revealed that the most prominent inhibitor, SF2, was safe in mice and effectively inhibited the in vitro growth of both free as well as in macrophage-internalized wild-type and drug-resistant Mtb clinical isolates. Notably, SF2 also showed a marginal reduction in the bacterial load in organs of mice infected with Mtb . Collectively, these findings advocate the chemical inhibition of IGPD of the His pathway as a novel anti- Mtb therapeutic strategy.