Methyl-Thiazoles: A Novel Mode of Inhibition with the Potential to Develop Novel Inhibitors Targeting InhA in Mycobacterium tuberculosis

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• 作者：Pravin S. Shirude ; Prashanti Madhavapeddi ; Maruti Naik ; Kannan Murugan ; Vikas Shinde ; Radha Nandishaiah ; Jyothi Bhat ; Anupriya Kumar ; Shahul Hameed ; Geoffrey Holdgate ; Gareth Davies ; Helen McMiken ; Naina Hegde ; Anisha Ambady ; Janani Venkatraman ; Manoranjan Panda ; Balachandra Bandodkar ; Vasan K. Sambandamurthy ; Jon A. Read
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：November 14, 2013
• 年：2013
• 卷：56
• 期：21
• 页码：8533-8542
• 全文大小：410K
• 年卷期：v.56,no.21(November 14, 2013)
• ISSN：1520-4804

文摘

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 鈥淵158-out鈥?inhibitor-bound conformation of the protein that accommodates a neutrally charged 鈥渨arhead鈥? 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 K_d of 13.7 nM, as against the NAD⁺-bound form of the enzyme.