This study describes the antibacterial properties of synthetically produced mixed aryl-alkyl
disulfide compounds as a means to control the growth of Staphylococcus aureus and Bacillus anthracis. Some of these compounds exerted strong in vitro bioactivity. Our results indicate that among the 12 different aryl substituents examined, nitrophenyl derivatives provide the strongest
antibiotic activities. This may be the result of electronic activation of the arylthio moiety as a leaving group for nucleophilic attack on the
disulfide bond. Small alkyl residues on the other
sulfur provide the best activity as well, which for different bacteria appears to be somewhat dependent on the nature of the alkyl moiety. The mechanism of action of these lipophilic
disulfides is likely similar to that of previously reported N-thiolated
beta-lactams, which have been shown to produce alkyl-
CoA disulfides through a
thiol-
disulfide exchange within the cytoplasm, ultimately inhibiting type II
fatty acid synthesis. However, the mixed alkyl-
CoA disulfides themselves show no antibacterial activity, presumably due to the inability of the highly polar compounds to cross the bacterial cell membrane. These structurally simple
disulfides have been found to inhibit
beta-ketoacyl-acyl carrier protein synthase III, or FabH, a key
enzyme in type II
fatty acid biosynthesis, and thus may serve as new leads to the development of effective antibacterials for MRSA and
anthrax infections.