Characterization of a triazole scaffold compound as an inhibitor of Mycobacterium tuberculosis imidazoleglycerol‐phosphate dehydratase

Abstract

Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis (TB), employs ten enzymes including imidazoleglycerol‐phosphate dehydratase (IGPD) for de novo biosynthesis of histidine. The absence of histidine‐biosynthesis in humans combined with its essentiality for Mtb makes the enzymes of this pathway major anti‐TB drug targets. We explored the inhibitory potential of a small molecule β‐(1,2,4‐Triazole‐3‐yl)‐DL‐alanine (DLA) against Mtb IGPD. DLA exhibits an in vitro inhibitory efficacy in the lower micromolar range. Higher‐resolution crystal structures of native and substrate‐bound Mtb IGPD provided additional structural features of this important drug target. Crystal structure of IGPD‐DLA complex at a resolution of 1.75 Å, confirmed that DLA locks down the function of the enzyme by binding in the active site pocket of the IGPD mimicking the substrate‐binding mode to a high degree. In our biochemical study, DLA showed an efficient inhibition of Mtb IGPD. Furthermore, DLA also showed bactericidal activity against Mtb and Mycobacterium smegmatis and inhibited their growth in respective culture medium. Importantly, owing to the favorable ADME and physicochemical properties, it serves as an important lead molecule for further derivatizations.

Targeting imidazole-glycerol phosphate dehydratase in plants: novel approach for structural and functional studies, and inhibitor blueprinting

“…However, based on our complex with IG2, these polar H-bonds are rather weak, with the donor-acceptor distances of 3.5 -3.8 Å. Participation of the corresponding Arg121 of Mycobacterium tuberculosis HisB in closing the active site has been pointed out recently by Kumar and coworkers (Kumar et al, 2022).…”

Chemical inhibition of histidine biosynthesis curtailsM. tuberculosisinfection

“…The availability of such a wealth of information provides a basis to examine whether triazole and imidazole scaffold inhibitors exhibit anti-TB potency by inhibiting the function of the His pathway of Mtb. Our earlier studies 12,13 and reports from other groups 16,18 suggest that triazole and imidazole derivatives compounds have better prospects in inhibiting the function of IGPD. The 3D experimental structure of this enzyme from Mtb has been elucidated by us 12 and from other organisms by others 20,21 .…”

“…Furthermore, the fundamental requirement of His for Mtb viability and the inability of humans to not make His de novo 11 make this pathway an attractive drug target. In a major focus to design new anti-TB small molecules with novel mechanism of action, over the years, we have structurally and biochemically characterized IGPD (also known as HisB) 12,13 , HisC 14 and HisN 15 of this pathway. Notably, primarily owing to the absence of its both structural and functional homologs in mammals, IGPD belongs to a prime category of anti-bacterial 13 , anti-herbs 16 and anti-fungal 17 drug target.…”

“…In a major focus to design new anti-TB small molecules with novel mechanism of action, over the years, we have structurally and biochemically characterized IGPD (also known as HisB) 12,13 , HisC 14 and HisN 15 of this pathway. Notably, primarily owing to the absence of its both structural and functional homologs in mammals, IGPD belongs to a prime category of anti-bacterial 13 , anti-herbs 16 and anti-fungal 17 drug target. In this study, through a target-based approach, we have identified a number of anti-HisB inhibitors and show that chemical inhibition of the Mtb de novo histidine biosynthesis leads to a significant bacterial clearance.…”

Protein targets in Mycobacterium tuberculosis and their inhibitors for therapeutic implications: A narrative review

“…The 6-hydroxymethyl-7, 8-dihydropteroate synthase (DHPS) is a pivotal enzyme in the folate biosynthetic pathway. It is been reported through in silico docking approaches that the tryptophan-lysine dipeptide has a higher efficiency than sulfa drugs in inhibiting DHPS, hence, it can be a promising lead compound for further studies on drug discovery [111]. Indole-3-glycerol phosphate synthase (IGPS) belongs to the tryptophan biosynthetic pathway.…”