title: Acetylene-based analogues of thiolactomycin, active against Mycobacterium tuberculosis mtFabH fatty acid condensing enzyme.
abstract: Analogues of the natural antibiotic thiolactomycin, with acetylene-based side chains, have the highest recorded in vitro inhibitory activity against the recombinant Mycobacterium tuberculosis beta-ketoacyl-ACP synthase mtFabH condensing enzyme. In particular, 5-[3-(4-acetyl-phenyl)-prop-2-ynyl]-4-hydroxy-3,5-dimethyl-5H-thiophen-2-one exhibited more than an 18-fold increased potency, compared to thiolactomycin, against this key condensing enzyme, involved in M. tuberculosis mycolic acid biosynthesis. Analogues of the antibiotic thiolactomycin, with acetylene-based side chains, have the highest recorded activity against cloned mtFabH condensing enzyme.
authors.affiliation: School of Biosciences, The University of Birmingham, B15 2TT, Edgbaston, Birmingham, UK
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Senior
authors.forename: Petr A
authors.initials: PA
authors.lastname: Illarionov
authors.forename: Sudagar S
authors.initials: SS
authors.lastname: Gurcha
authors.forename: Ian B
authors.initials: IB
authors.lastname: Campbell
authors.forename: Merrill L
authors.initials: ML
authors.lastname: Schaeffer
authors.forename: David E
authors.initials: DE
authors.lastname: Minnikin
authors.forename: Gurdyal S
authors.initials: GS
authors.lastname: Besra
mesh_terms: D000114:Acetylene / Q000031:analogs & derivatives* / Q000494:pharmacology; D000123:Acetyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D054889:Fatty Acid Synthase, Type II; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology*; D013876:Thiophenes / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D013876:Thiophenes; C035068:thiolactomycin; D000123:Acetyltransferases; D064429:Fatty Acid Synthases; D054889:Fatty Acid Synthase, Type II; C413881:fatty acid synthase I, mycobacteria; D000114:Acetylene