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Thiolactomycin and Related Analogues as Novel Anti-mycobacterial Agents Targeting KasA and KasB Condensing Enzymes in Mycobacterium tuberculosis

Lookup NU author(s): Mark Guy, Dr Lynn Dover, Professor Jeremy LakeyORCiD, Professor David Minnikin

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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 β- 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.


Publication metadata

Author(s): Dover LG; Minnikin DE; Lakey JH; Guy MR; Kremer L; Brennan PJ; Besra GS; Douglas JD; Baulard AR; Morehouse C; Alland D; Jacobs Jr WR

Publication type: Article

Publication status: Published

Journal: Journal of Biological Chemistry

Year: 2000

Volume: 275

Issue: 22

Pages: 16857-16864

ISSN (print): 0021-9258

ISSN (electronic): 1083-351X

Publisher: American Society for Biochemistry and Molecular Biology

URL: http://dx.doi.org/10.1074/jbc.M000569200

DOI: 10.1074/jbc.M000569200

PubMed id: 10747933


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Funding

Funder referenceFunder name
AI-43268NIAID NIH HHS
AI-18357NIAID NIH HHS
AI-33706NIAID NIH HHS

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