Thiolactomycin and Related Analogues as Novel Anti-mycobacterial Agents Targeting KasA and KasB Condensing Enzymes inMycobacterium tuberculosis
| Autor: | James D. Douglas, Caroline B. Morehouse, Laurent Kremer, Lynn G. Dover, David Alland, Gurdyal S. Besra, Alain R. Baulard, Jeremy H. Lakey, William R. Jacobs, Mark R. Guy, David E. Minnikin, Patrick J. Brennan |
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| Rok vydání: | 2000 |
| Předmět: |
Tuberculosis
Protein Conformation Antitubercular Agents Thiophenes Biochemistry Microbiology Mycobacterium tuberculosis In vivo medicine Molecular Biology chemistry.chemical_classification Mycobacterium bovis Sequence Homology Amino Acid biology Fatty acid Cell Biology biology.organism_classification medicine.disease In vitro Amino acid Isoenzymes Alcohol Oxidoreductases Enzyme Mycolic Acids chemistry 3-Oxoacyl-(Acyl-Carrier-Protein) Reductase |
| Zdroj: | Journal of Biological Chemistry. 275:16857-16864 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m000569200 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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