Antimycobacterial activity of cerulenin and its effects on lipid biosynthesis

Cerulenin is a potent inhibitor of fatty acid synthase (FAS) in a variety o f prokaryotic and eukaryotic cells. Using a standardized mycobacterial susc eptibility test, we have observed that cerulenin inhibits the growth of sev eral species of mycobacteria, including tuberculous species such as Mycobac terium tuberculosis (H37Rv and clinical isolates) and Mycobacterium bovis B CG (hereafter called BCG), as well as several non-tuberculous species: Myco bacterium smegmatis, the Mycobacterium avium-intracellulare complex (MAC), Mycobacterium kansasii and others. All species and strains tested, includin g multi-drug resistant isolates of M. tuberculosis, were susceptible to cer ulenin with MICs ranging from 1.5 to 12.5 mg/L. Two-dimensional thin-layer chromatography revealed different inhibition patterns of lipid synthesis be tween tuberculous and non-tuberculous mycobacteria. Cerulenin treatment res ulted in a relative increase in phospholipids and mycolic acids in MAC and M. smegmatis, whereas in cerulenin-treated BCG, phospholipids and mycolic a cids diminished relative to controls. In addition, long-chain extractable l ipids (intermediate in polarity), triglycerides and glycopeptidolipids decr eased with cerulenin treatment in all three species of mycobacteria tested. Qualitative changes in several of these lipid classes indicate inhibition in the synthesis of intermediate and long-chain fatty acids. Our results su ggest that cerulenin's primary effect may be inhibition of intermediate and long-chain lipid synthesis, with little effect on the synthesis of other l ipid classes. In addition, the BCG-specific reduction in phospholipids and mycolic acids suggests the presence of a unique cerulenin-sensitive FAS sys tem in tuberculous mycobacteria. Since pathogenic mycobacteria produce nove l long-chain fatty acids, inhibition of fatty acid synthesis offers a poten tial target for the development of antimycobacterial drugs.