Thiolactomycin and related analogues as novel anti-mycobacterial agents targeting KasA and KasB condensing enzymes in Mycobacterium tuberculosis

Prevention efforts and control of tuberculosis are seriously hampered by th e appearance of multidrug-resistant strains of Mycobacterium tuberculosis, dictating new approaches to the treatment of the disease. Thiolactomycin (T LM) is a unique thiolactone that has been shown to exhibit anti-mycobacteri al activity by specifically inhibiting fatty acid and mycolic acid biosynth esis. In this study, we present evidence that TLM targets two beta-ketoacyl -acyl-carrier protein synthases, KasA and KasB, consistent with the fact th at both enzymes belong to the fatty-acid synthase type II system involved i n fatty acid and mycolic acid biosynthesis. Overexpression of KasA, KasB, a nd KasAB in Mycobacterium bovis BCG increased in vivo and in vitro resistan ce against TLM. In addition, a multidrug-resistant clinical isolate was als o 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 ag ainst fatty acid and mycolic acid biosynthesis and in vivo against M. tuber culosis. Finally, a three-dimensional structural model of KasA has also bee n 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.