Antibacterial FabH Inhibitors with Mode of Action Validated in Haemophilus influenzae by in Vitro Resistance Mutation Mapping

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• 作者：David C. McKinney ; Charles J. Eyermann ; Rong-Fang Gu ; Jun Hu ; Steven L. Kazmirski ; Sushmita D. Lahiri ; Andrew R. McKenzie ; Adam B. Shapiro ; Gloria Breault
• 刊名：ACS Infectious Diseases
• 出版年：2016
• 出版时间：July 8, 2016
• 年：2016
• 卷：2
• 期：7
• 页码：456-464
• 全文大小：740K
• ISSN：2373-8227

文摘

Fatty acid biosynthesis is essential to bacterial growth in Gram-negative pathogens. Several small molecules identified through a combination of high-throughput and fragment screening were cocrystallized with FabH (β-ketoacyl-acyl carrier protein synthase III) from Escherichia coli and Streptococcus pneumoniae. Structure-based drug design was used to merge several scaffolds to provide a new class of inhibitors. After optimization for Gram-negative enzyme inhibitory potency, several compounds demonstrated antimicrobial activity against an efflux-negative strain of Haemophilus influenzae. Mutants resistant to these compounds had mutations in the FabH gene near the catalytic triad, validating FabH as a target for antimicrobial drug discovery.