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.
Keywords:
FabH; FasII; antibacterial; fatty acid biosynthesis; structure-based drug design; β-ketoacyl-acyl carrier protein synthase III.
MeSH terms
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3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / antagonists & inhibitors*
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3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / chemistry
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3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / genetics
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3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / metabolism
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Anti-Bacterial Agents / chemistry
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Anti-Bacterial Agents / pharmacology*
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Bacterial Proteins / antagonists & inhibitors*
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Bacterial Proteins / genetics
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Bacterial Proteins / metabolism
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Drug Design
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Drug Resistance, Bacterial*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Haemophilus Infections / microbiology
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Haemophilus influenzae / chemistry
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Haemophilus influenzae / drug effects
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Haemophilus influenzae / enzymology*
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Haemophilus influenzae / genetics
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Humans
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Microbial Sensitivity Tests
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Mutation
Substances
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Anti-Bacterial Agents
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Bacterial Proteins
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Enzyme Inhibitors
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3-ketoacyl-acyl carrier protein synthase III
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3-Oxoacyl-(Acyl-Carrier-Protein) Synthase