title: Dual inhibition of mycobacterial fatty acid biosynthesis and degradation by 2-alkynoic acids.
abstract: 2-Hexadecynoic acid and 2-octadecynoic acid have cidal activity against Mycobacterium smegmatis and Mycobacterium bovis BCG. At subinhibitory concentrations, M. smegmatis rapidly transformed [1-(14)C]-2-hexadecynoic acid into endogenous fatty acids and elongated them into mycolic acids. Toxic concentrations of 2-hexadecynoic acid resulted in accumulation of 3-ketohexadecanoic acid, which blocked fatty acid biosynthesis, and 3-hexadecynoic acid, an inhibitor of fatty acid degradation. The combination of these two metabolites is necessary to achieve the inhibition of M. smegmatis. We conclude that 2- and 3-hexa/octadecynoic acids inhibit mycolic acid biosynthesis, fatty acid biosynthesis, and fatty acid degradation, pathways of significant importance for mycobacteria.
authors.affiliation: Department of Microbiology and Immunology, Howard Hughes Medical Institute, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
authors.forename: Hector R
authors.initials: HR
authors.lastname: Morbidoni
authors.forename: Catherine
authors.initials: C
authors.lastname: Vilchèze
authors.forename: Laurent
authors.initials: L
authors.lastname: Kremer
authors.forename: Robert
authors.initials: R
authors.lastname: Bittman
authors.forename: James C
authors.initials: JC
authors.lastname: Sacchettini
authors.forename: William R
authors.initials: WR
authors.lastname: Jacobs
mesh_terms: D000480:Alkynes / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D005227:Fatty Acids / Q000096:biosynthesis / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D008956:Models, Chemical; D009161:Mycobacterium / Q000187:drug effects* / Q000378:metabolism; D009163:Mycobacterium bovis / Q000187:drug effects / Q000378:metabolism; D020102:Mycobacterium smegmatis / Q000187:drug effects / Q000378:metabolism; D009171:Mycolic Acids / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C511879:2-octadecynoic acid; D000480:Alkynes; D000900:Anti-Bacterial Agents; D005227:Fatty Acids; D005231:Fatty Acids, Unsaturated; D009171:Mycolic Acids; C031203:2-hexadecynoic acid