Methyl-thiazoles: a novel mode of inhibition with the potential to develop novel inhibitors targeting InhA in Mycobacterium tuberculosis.
Shirude PS, Madhavapeddi P, Naik M, Murugan K, Shinde V, Nandishaiah R, Bhat J, Kumar A, Hameed S, Holdgate G, Davies G, McMiken H, Hegde N, Ambady A, Venkatraman J, Panda M, Bandodkar B, Sambandamurthy VK, Read JA.
InhA is a well validated Mycobacterium tuberculosis (Mtb) target as evidenced by the clinical success of isoniazid. Translating enzyme inhibition to bacterial cidality by targeting the fatty acid substrate site of InhA remains a daunting challenge. The recent disclosure of a methyl-thiazole series demonstrates that bacterial cidality can be achieved with potent enzyme inhibition and appropriate physicochemical properties. In this study, we report the molecular mode of action of a lead methyl-thiazole, along with analogues with improved CYP inhibition profile. We have identified a novel mechanism of InhA inhibition characterized by a hitherto unreported 'Y158-out' inhibitor-bound conformation of the protein that accommodates a neutrally charged 'warhead'. An additional novel hydrophilic interaction with protein residue M98 allows the incorporation of favorable physicochemical properties for cellular activity. Notably, the methyl-thiazole prefers the NADH-bound form of the enzyme with a Kd of ~13.7 nM, as against the NAD(+)-bound form of the enzyme.