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Antimicrobial Agents and Chemotherapy, April 2001, p. 1143-1150, Vol. 45, No. 4
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.4.1143-1150.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

In Vitro Activity of a Novel Antimycobacterial Compound, N-Octanesulfonylacetamide, and Its Effects on Lipid and Mycolic Acid Synthesis

Nikki M. Parrish,1 Todd Houston,2,dagger Paul B. Jones,2,Dagger Craig Townsend,2 and James D. Dick1,3,*

Department of Pathology, School of Medicine,1 Department of Molecular Microbiology and Immunology, School of Public Health,3 and Department of Chemistry, Johns Hopkins School of Arts and Sciences,2 Johns Hopkins University, Baltimore, Maryland

Received 29 September 2000/Returned for modification 8 November 2000/Accepted 22 January 2001

beta -Sulfonyl carboxamides have been proposed to serve as transition-state analogues of the beta -ketoacyl synthase reaction involved in fatty acid elongation. We tested the efficacy of N-octanesulfonylacetamide (OSA) as an inhibitor of fatty acid and mycolic acid biosynthesis in mycobacteria. Using the BACTEC radiometric growth system, we observed that OSA inhibits the growth of several species of slow-growing mycobacteria, including Mycobacterium tuberculosis (H37Rv and clinical isolates), the Mycobacterium avium complex (MAC), Mycobacterium bovis BCG, Mycobacterium kansasii, and others. Nearly all species and strains tested, including isoniazid and multidrug resistant isolates of M. tuberculosis, were susceptible to OSA, with MICs ranging from 6.25 to 12.5 µg/ml. Only three clinical isolates of M. tuberculosis (CSU93, OT2724, and 401296), MAC, and Mycobacterium paratuberculosis required an OSA MIC higher than 25.0 µg/ml. Rapid-growing mycobacterial species, such as Mycobacterium smegmatis, Mycobacterium fortuitum, and others, were not susceptible at concentrations of up to 100 µg/ml. A 2-dimensional thin-layer chromatography system showed that OSA treatment resulted in a significant decrease in all species of mycolic acids present in BCG. In contrast, mycolic acids in M. smegmatis were relatively unaffected following exposure to OSA. Other lipids, including polar and nonpolar extractable classes, were unchanged following exposure to OSA in both BCG and M. smegmatis. Transmission electron microscopy of OSA-treated BCG cells revealed a disruption in cell wall synthesis and incomplete septum formation. Our results indicate that OSA inhibits the growth of several species of mycobacteria, including both isoniazid-resistant and multidrug resistant strains of M. tuberculosis. This inhibition may be the result of OSA-mediated effects on mycolic acid synthesis in slow-growing mycobacteria or inhibition via an undescribed mechanism. Our results indicate that OSA may serve as a promising lead compound for future antituberculous drug development.

* Corresponding author. Mailing address: Johns Hopkins Medical Institutions, Department of Pathology/Division of Medical Microbiology, 600 N. Wolfe St., Baltimore, MD 21287. Phone: (410) 955-5077. Fax: (410) 614-8087. E-mail: jdick{at}jhmi.edu.

dagger Present address: Department of Chemistry, Virginia Commonwealth University, Richmond, Va.

Dagger Present address: Department of Chemistry, Wake Forest University, Winston-Salem, N.C.

Antimicrobial Agents and Chemotherapy, April 2001, p. 1143-1150, Vol. 45, No. 4
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.4.1143-1150.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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