title: Thiolactomycin and related analogues as novel anti-mycobacterial agents targeting KasA and KasB condensing enzymes in Mycobacterium tuberculosis.
abstract: Prevention efforts and control of tuberculosis are seriously hampered by the appearance of multidrug-resistant strains of Mycobacterium tuberculosis, dictating new approaches to the treatment of the disease. Thiolactomycin (TLM) is a unique thiolactone that has been shown to exhibit anti-mycobacterial activity by specifically inhibiting fatty acid and mycolic acid biosynthesis. In this study, we present evidence that TLM targets two beta-ketoacyl-acyl-carrier protein synthases, KasA and KasB, consistent with the fact that both enzymes belong to the fatty-acid synthase type II system involved in fatty acid and mycolic acid biosynthesis. Overexpression of KasA, KasB, and KasAB in Mycobacterium bovis BCG increased in vivo and in vitro resistance against TLM. In addition, a multidrug-resistant clinical isolate was also found to be highly sensitive to TLM, indicating promise in counteracting multidrug-resistant strains of M. tuberculosis. The design and synthesis of several TLM derivatives have led to compounds more potent both in vitro against fatty acid and mycolic acid biosynthesis and in vivo against M. tuberculosis. Finally, a three-dimensional structural model of KasA has also been generated to improve understanding of the catalytic site of mycobacterial Kas proteins and to provide a more rational approach to the design of new drugs.
authors.affiliation: Departments of Microbiology and Immunology and Chemistry, School of Biochemistry and Genetics, University of Newcastle upon Tyne, Newcastle upon Tyne, NE2 4HH England, INSERM U447.
authors.forename: L
authors.initials: L
authors.lastname: Kremer
authors.forename: J D
authors.initials: JD
authors.lastname: Douglas
authors.forename: A R
authors.initials: AR
authors.lastname: Baulard
authors.forename: C
authors.initials: C
authors.lastname: Morehouse
authors.forename: M R
authors.initials: MR
authors.lastname: Guy
authors.forename: D
authors.initials: D
authors.lastname: Alland
authors.forename: L G
authors.initials: LG
authors.lastname: Dover
authors.forename: J H
authors.initials: JH
authors.lastname: Lakey
authors.forename: W R
authors.initials: WR
authors.lastname: Jacobs
authors.forename: P J
authors.initials: PJ
authors.lastname: Brennan
authors.forename: D E
authors.initials: DE
authors.lastname: Minnikin
authors.forename: G S
authors.initials: GS
authors.lastname: Besra
mesh_terms: D064431:3-Oxoacyl-(Acyl-Carrier-Protein) Reductase; D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000995:Antitubercular Agents / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000737:chemistry; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009171:Mycolic Acids / Q000378:metabolism; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013876:Thiophenes / Q000494:pharmacology
chemical_list: D000995:Antitubercular Agents; D007527:Isoenzymes; D009171:Mycolic Acids; D013876:Thiophenes; C035068:thiolactomycin; D000429:Alcohol Oxidoreductases; D064431:3-Oxoacyl-(Acyl-Carrier-Protein) Reductase