Aminopyrazinamides: Novel and Specific GyrB Inhibitors that Kill Replicating and Nonreplicating Mycobacterium tuberculosis

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• 作者：Pravin S. Shirude ; Prashanti Madhavapeddi ; Julie A. Tucker ; Kannan Murugan ; Vikas Patil ; Halesha Basavarajappa ; Anandkumar V. Raichurkar ; Vaishali Humnabadkar ; Syeed Hussein ; Sreevalli Sharma ; V. K. Ramya ; Chandan B. Narayan ; Tanjore S. Balganesh ; Vasan K. Sambandamurthy
• 刊名：ACS Chemical Biology
• 出版年：2013
• 出版时间：March 15, 2013
• 年：2013
• 卷：8
• 期：3
• 页码：519-523
• 全文大小：297K
• 年卷期：v.8,no.3(March 15, 2013)
• ISSN：1554-8937

文摘

Aminopyrazinamides originated from a high throughput screen targeting the Mycobacterium smegmatis (Msm) GyrB ATPase. This series displays chemical tractability, robust structure鈥揳ctivity relationship, and potent antitubercular activity. The crystal structure of Msm GyrB in complex with one of the aminopyrazinamides revealed promising attributes of specificity against other broad spectrum pathogens and selectivity against eukaryotic kinases due to novel interactions at hydrophobic pocket, unlike other known GyrB inhibitors. The aminopyrazinamides display excellent mycobacterial kill under in vitro, intracellular, and hypoxic conditions.