title: Staphylococcus aureus FabI: inhibition, substrate recognition, and potential implications for in vivo essentiality.
abstract: Methicillin-resistant Staphylococcus aureus (MRSA) infections constitute a serious health threat worldwide, and novel antibiotics are therefore urgently needed. The enoyl-ACP reductase (saFabI) is essential for the S. aureus fatty acid biosynthesis and, hence, serves as an attractive drug target. We have obtained a series of snapshots of this enzyme that provide a mechanistic picture of ligand and inhibitor binding, including a dimer-tetramer transition combined with extensive conformational changes. Significantly, our results reveal key differences in ligand binding and recognition compared to orthologous proteins. The remarkable observed protein flexibility rationalizes our finding that saFabI is capable of efficiently reducing branched-chain fatty acid precursors. Importantly, branched-chain fatty acids represent a major fraction of the S. aureus cell membrane and are crucial for its in vivo fitness. Our discovery thus addresses a long-standing controversy regarding the essentiality of the fatty acid biosynthesis pathway in S. aureus rationalizing saFabI as a drug target.
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, Institute for Structural Biology, University of Würzburg, D-97080 Würzburg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Schiebel
authors.forename: Andrew
authors.initials: A
authors.lastname: Chang
authors.forename: Hao
authors.initials: H
authors.lastname: Lu
authors.forename: Michael V
authors.initials: MV
authors.lastname: Baxter
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Tonge
authors.forename: Caroline
authors.initials: C
authors.lastname: Kisker
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D008969:Molecular Sequence Data; D011487:Protein Conformation; D013211:Staphylococcus aureus / Q000201:enzymology* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D001426:Bacterial Proteins; D005227:Fatty Acids; D008024:Ligands; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)