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Originally published In Press as doi:10.1074/jbc.M000569200 on March 15, 2000

J. Biol. Chem., Vol. 275, Issue 22, 16857-16864, June 2, 2000
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Thiolactomycin and Related Analogues as Novel Anti-mycobacterial Agents Targeting KasA and KasB Condensing Enzymes in Mycobacterium tuberculosis*

Laurent Kremerab, James D. Douglascd, Alain R. Baularde, Caroline Morehousea, Mark R. Guyac, David Allandf, Lynn G. Dovera, Jeremy H. Lakeyg, William R. Jacobs Jr.h, Patrick J. Brennani, David E. Minnikinc, and Gurdyal S. Besraaj

From the Departments of a Microbiology and Immunology and c Chemistry, g School of Biochemistry and Genetics, University of Newcastle upon Tyne, Newcastle upon Tyne, NE2 4HH England, e INSERM U447, Institut Pasteur de Lille, 59019 Lille, France, the f Division of Infectious Diseases, Department of Medicine, Montefiore Medical Center, Bronx, New York 10467, the h Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York, 10461, and the i Department of Microbiology, Colorado State University, Fort Collins, Colorado 80523-1677

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.

* This work was supported by the Medical Research Council (United Kingdom); by NIAID, National Institutes of Health Grants AI-18357, AI-33706, and AI-43268; and by Cooperative Agreement AI-38087 from the National Cooperative Drug Discovery Groups for the Treatment of Opportunistic Infections, NIAID, National Institutes of Health.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

b Supported through a Heiser Trust postdoctoral fellowship.

d Holder of a United Kingdom Engineering and Physical Research Council Quota studentship.

j A Lister Institute-Jenner Research Fellow. To whom correspondence should be addressed. Tel.: 0191-222-5412; Fax: 0191-222-7736; E-mail: g.s.besra@newcastle.ac.uk.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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