Pyrazolopyrimidines Establish MurC as a Vulnerable Target in Pseudomonas aeruginosa and Escherichia coli

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• 作者：Shahul Hameed P ; Praveena Manjrekar ; Murugan Chinnapattu ; Vaishali Humnabadkar ; Gajanan Shanbhag ; Chaitanyakumar Kedari ; Naina Vinay Mudugal ; Anisha Ambady ; Boudewijn L.M. de Jonge ; Claire Sadler ; Beena Paul ; Shubha Sriram ; Parvinder Kaur ; Supreeth Guptha ; Anandkumar Raichurkar ; Paul Fleming ; Charles J. Eyermann ; David C. McKinney ; Vasan K. Sambandamurthy ; Manoranjan Panda ; Sudha Ravishankar
• 刊名：ACS Chemical Biology
• 出版年：2014
• 出版时间：October 17, 2014
• 年：2014
• 卷：9
• 期：10
• 页码：2274-2282
• 全文大小：457K
• ISSN：1554-8937

文摘

The bacterial peptidoglycan biosynthesis pathway provides multiple targets for antibacterials, as proven by the clinical success of 尾-lactam and glycopeptide classes of antibiotics. The Mur ligases play an essential role in the biosynthesis of the peptidoglycan building block, N-acetyl-muramic acid-pentapeptide. MurC, the first of four Mur ligases, ligates l-alanine to UDP-N-acetylmuramic acid, initiating the synthesis of pentapeptide precursor. Therefore, inhibiting the MurC enzyme should result in bacterial cell death. Herein, we report a novel class of pyrazolopyrimidines with subnanomolar potency against both Escherichia coli and Pseudomonas aeruginosa MurC enzymes, which demonstrates a concomitant bactericidal activity against efflux-deficient strains. Radio-labeled precursor incorporation showed these compounds selectively inhibited peptidoglycan biosynthesis, and genetic studies confirmed the target of pyrazolopyrimidines to be MurC. In the presence of permeability enhancers such as colistin, pyrazolopyrimidines exhibited low micromolar MIC against the wild-type bacteria, thereby, indicating permeability and efflux as major challenges for this chemical series. Our studies provide biochemical and genetic evidence to support the essentiality of MurC and serve to validate the attractiveness of target for antibacterial discovery.