PDBsum entry 4z8d

Transferase/transferase inhibitor

PDB id: 4z8d

Contents

Protein chains

317 a.a.

Ligands

4LB ×2

SO4 ×2

Waters ×310

PDB id:

4z8d

Name:

Transferase/transferase inhibitor

Title:

Antibacterial fabh inhibitors with validated mode of action in haemophilus influenzae by in vitro resistance mutation mapping

Structure:

3-oxoacyl-[acyl-carrier-protein] synthase 3. Chain: a, b. Synonym: 3-oxoacyl-[acyl-carrier-protein] synthase iii,beta-ketoacyl- acp synthase iii,kas iii. Engineered: yes

Source:

Escherichia coli o157:h7. Organism_taxid: 83334. Gene: fabh, z1730, ecs1469. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.00Å R-factor: 0.161 R-free: 0.215

Authors:

S.D.Lahiri

Key ref:

D.C.McKinney et al. (2016). Antibacterial FabH Inhibitors with Mode of Action Validated in Haemophilus influenzae by in Vitro Resistance Mutation Mapping. Acs Infect Dis, 2, 456-464. PubMed id: 27626097 DOI: 10.1021/acsinfecdis.6b00053

Date:

08-Apr-15 Release date: 04-May-16

Protein chains

P0A6R0  (FABH_ECOLI) -  Beta-ketoacyl-[acyl-carrier-protein] synthase III from Escherichia coli (strain K12)

Seq: 317 a.a.

Struc: 317 a.a.

Enzyme reactions

• Enzyme class: E.C.2.3.1.180 - beta-ketoacyl-[acyl-carrier-protein] synthase Iii.
• Reaction: malonyl-[ACP] + acetyl-CoA + H⁺ = 3-oxobutanoyl-[ACP] + CO2 + CoA

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/acsinfecdis.6b00053

Acs Infect Dis 2:456-464 (2016)

PubMed id: 27626097

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

D.C.McKinney, C.J.Eyermann, R.F.Gu, J.Hu, S.L.Kazmirski, S.D.Lahiri, A.R.McKenzie, A.B.Shapiro, G.Breault.

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.