4Z8D

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

Summary for 4Z8D

• Entry DOI: 10.2210/pdb4z8d/pdb
• Descriptor: 3-oxoacyl-[acyl-carrier-protein] synthase 3, trans-4-[({[(2-chlorobenzyl)oxy]carbonyl}amino)methyl]cyclohexanecarboxylic acid, SULFATE ION, ... (4 entities in total)
• Functional Keywords: beta-ketoacyl-(acyl-carrier-protein) synthase iii, carbamate, structure based drug design, fatty acid biosynthesis, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Escherichia coli O157:H7
• Cellular location: Cytoplasm : P0A6R2
• Total number of polymer chains: 2
• Total formula weight: 67937.75

Authors

Lahiri, S.D. (deposition date: 2015-04-08, release date: 2016-05-04, Last modification date: 2024-03-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2 Å)