title: Activation of Exogenous Fatty Acids to Acyl-Acyl Carrier Protein Cannot Bypass FabI Inhibition in Neisseria.
abstract: Neisseria is a Gram-negative pathogen with phospholipids composed of straight chain saturated and monounsaturated fatty acids, the ability to incorporate exogenous fatty acids, and lipopolysaccharides that are not essential. The FabI inhibitor, AFN-1252, was deployed as a chemical biology tool to determine whether Neisseria can bypass the inhibition of fatty acid synthesis by incorporating exogenous fatty acids. Neisseria encodes a functional FabI that was potently inhibited by AFN-1252. AFN-1252 caused a dose-dependent inhibition of fatty acid synthesis in growing Neisseria, a delayed inhibition of growth phenotype, and minimal inhibition of DNA, RNA, and protein synthesis, showing that its mode of action is through inhibiting fatty acid synthesis. Isotopic fatty acid labeling experiments showed that Neisseria encodes the ability to incorporate exogenous fatty acids into its phospholipids by an acyl-acyl carrier protein-dependent pathway. However, AFN-1252 remained an effective antibacterial when Neisseria were supplemented with exogenous fatty acids. These results demonstrate that extracellular fatty acids are activated by an acyl-acyl carrier protein synthetase (AasN) and validate type II fatty acid synthesis (FabI) as a therapeutic target against Neisseria.
authors.affiliation: From the Departments of Infectious Diseases and.
authors.forename: Jiangwei
authors.initials: J
authors.lastname: Yao
authors.affiliation: Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
authors.forename: David F
authors.initials: DF
authors.lastname: Bruhn
authors.affiliation: From the Departments of Infectious Diseases and.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Frank
authors.affiliation: Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Lee
authors.affiliation: From the Departments of Infectious Diseases and charles.rock@stjude.org.
authors.forename: Charles O
authors.initials: CO
authors.lastname: Rock
mesh_terms: D000213:Acyl Carrier Protein / Q000378:metabolism*; D001426:Bacterial Proteins / Q000302:isolation & purification / Q000378:metabolism*; D001572:Benzofurans / Q000494:pharmacology; D003066:Coenzyme A Ligases / Q000378:metabolism; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D005227:Fatty Acids / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008954:Models, Biological; D009343:Neisseria / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D010743:Phospholipids / Q000378:metabolism; D011753:Pyrones / Q000494:pharmacology; D013912:Threonine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C521531:API 1252; D000213:Acyl Carrier Protein; D001426:Bacterial Proteins; D001572:Benzofurans; C525369:CHIR 090; D005227:Fatty Acids; D006877:Hydroxamic Acids; D008070:Lipopolysaccharides; D010743:Phospholipids; D011753:Pyrones; D013912:Threonine; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); D003066:Coenzyme A Ligases
keywords: Neisseria; acyl carrier protein (ACP); antibiotics; bacterial metabolism; fatty acid; fatty acid synthase (FAS)