4Z8D

Antibacterial FabH Inhibitors with Validated Mode of Action in Haemophilus Influenzae by in vitro resistance mutation mapping

4Z8D の概要

• エントリーDOI: 10.2210/pdb4z8d/pdb
• 分子名称: 3-oxoacyl-[acyl-carrier-protein] synthase 3, trans-4-[({[(2-chlorobenzyl)oxy]carbonyl}amino)methyl]cyclohexanecarboxylic acid, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: beta-ketoacyl-(acyl-carrier-protein) synthase iii, carbamate, structure based drug design, fatty acid biosynthesis, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Escherichia coli O157:H7
• 細胞内の位置: Cytoplasm : P0A6R2
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 67937.75

構造登録者

Lahiri, S.D. (登録日: 2015-04-08, 公開日: 2016-05-04, 最終更新日: 2024-03-06)

主引用文献

McKinney, D.C.,Eyermann, C.J.,Gu, R.F.,Hu, J.,Kazmirski, S.L.,Lahiri, S.D.,McKenzie, A.R.,Shapiro, A.B.,Breault, G.
Antibacterial FabH Inhibitors with Mode of Action Validated in Haemophilus influenzae by in Vitro Resistance Mutation Mapping.
Acs Infect Dis., 2:456-464, 2016

PubMed Abstract: 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.

PubMed: 27626097
DOI: 10.1021/acsinfecdis.6b00053

実験手法

X-RAY DIFFRACTION (2 Å)