In vitro activity of a novel antimycobacterial compound, N-octanesulfonylacetamide, and its effects on lipid and mycolic acid synthesis

beta -Sulfonyl carboxamides have been proposed to serve as transition-state analogues of the beta -ketoacyl synthase reaction involved in fatty acid e longation. We tested the efficacy of N-octanesulfonylacetamide (OSA) as an inhibitor of fatty acid and mycolic acid biosynthesis in mycobacteria. Usin g the BACTEC radiometric growth system, we observed that OSA inhibits the g rowth of several species of slow-growing mycobacteria, including Mycobacter ium tuberculosis (H37Rv and clinical isolates), the Mycobacterium avium com plex (MAC), Mycobacterium bovis BCG, Mycobacterium kansasii, and others. Ne arly all species and strains tested, including isoniazid and multidrug resi stant isolates of M. tuberculosis, were susceptible to OSA, with MICs rangi ng from 6.25 to 12.5 mug/ml, Only three clinical isolates of M, tuberculosi s (CSU93, OT2724, and 401296), MAC, and Mycobacterium paratuberculosis requ ired an OSA MIC higher than 25.0 mug/ml. Rapid-growing mycobacterial specie s, such as Mycobacterium smegmatis, Mycobacterium fortuitum, and others, we re not susceptible at concentrations of up to 100 mug/ml. A a-dimensional t hin-layer chromatography system showed that OSA treatment resulted in a sig nificant decrease in all species of mycotic acids present in BCG, In contra st, mycolic acids in M, smegmatis were relatively unaffected following expo sure to OSA, Other lipids, including polar and nonpolar extractable classes , were unchanged following exposure to OSA in both BCG and M, smegmatis, Tr ansmission electron microscopy of OSA-treated BCG cells revealed a disrupti on in cell wall synthesis and incomplete septum formation. Our results indi cate that OSA inhibits the growth of several species of mycobacteria, inclu ding both isoniazid-resistant and multidrug resistant strains of M. tubercu losis. This inhibition may be the result of OSA-mediated effects on mycolic acid synthesis in slow-growing mycobacteria or inhibition via an undescrib ed mechanism. Our results indicate that OSA may serve as a promising lead c ompound for future antituberculous drug development.