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JAC Advance Access published online on September 8, 2004
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkh408
© 2004 by The British Society for Antimicrobial Chemotherapy
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Received May 5, 2004
Revised July 16, 2004
Accepted July 19, 2004

Original article

Effect of n-octanesulphonylacetamide (OSA) on ATP and protein expression in Mycobacterium bovis BCG

Nicole M. Parrish 1, Chiew G. Ko 1, Minerva A. Hughes 2, Craig A. Townsend 2, and James D. Dick 1*

1 Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
2 Department of Chemistry, Johns Hopkins School of Arts and Sciences, Johns Hopkins University, Baltimore, MD, USA

* To whom correspondence should be addressed. E-mail: jdick{at}jhmi.edu.


  Abstract

Objective: To determine the effect on BCG of n-octanesulphonylacetamide (OSA), a novel compound of the class {beta}-sulphonylcarboxamides, which has potent in vitro activity against pathogenic mycobacteria.

Methods and results: The effect of OSA in BCG was examined using two-dimensional protein electrophoresis. Treatment of BCG with OSA resulted in overexpression of two proteins identified as the b-subunit of ATP synthase (Rv1306) and a 17 kDa heat shock protein (Rv0251c). [35S]Methionine pulse-labelling revealed that overexpression occurred within as little as 3.5 h post-exposure. These results were confirmed by RT-PCR. ATP levels decreased in OSA-treated BCG at 5 min, and 1, 3 and 24 h, with a 64%, 45%, 54% and 73% reduction in ATP, respectively. Only dicyclohexylcarbodiimide (DCCD), a known ATP synthase inhibitor, had a similar effect. No appreciable difference in ATP level was observed in BCG treated with standard antimycobacterial drugs, additional respiratory chain inhibitors or a fatty acid synthase inhibitor at a comparable time-point. Protein synthesis decreased within 5 min of exposure to OSA (56%), DCCD (74%) and thenoyltrifluoroacetone (TTFA) (77%). Ethanol (2.3%) potentiated the activity of OSA. In contrast, no synergic effect was observed with streptomycin and ethanol. Mycolic acid levels decreased 79% with DCCD, 46% with TTFA, a complex II inhibitor, and 43% with OSA compared with untreated controls.

Conclusions. Our results suggest that OSA may interfere directly or indirectly with ATP synthase and possibly other components of the mycobacterial respiratory chain. These effects may hinder energy production, leading to interruption in the synthesis of large macromolecules including proteins and mycolic acids.

Keywords: growth inhibition; mycobacterial respiration; mycolic acids; ethanol metabolism; 2-D protein electrophoresis.
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