Unsymmetric aryl-alkyl disulfide growth inhibitors of methicillin-resistant Staphylococcus aureus and Bacillus anthracis.
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.
Turos
Edward
E
Center for Molecular Diversity in Drug Design, Discovery, and Delivery, Department of Chemistry, 4202 East Fowler Avenue, CHE 205, University of South Florida, Tampa, FL 33620, USA. eturos@cas.usf.edu
Revell
Kevin D
KD
Ramaraju
Praveen
P
Gergeres
Danielle A
DA
Greenhalgh
Kerriann
K
Young
Ashley
A
Sathyanarayan
Nalini
N
Dickey
Sonja
S
Lim
Daniel
D
Alhamadsheh
Mamoun M
MM
Reynolds
Kevin
K
D000478:Alkylation; D001408:Bacillus anthracis / Q000166:cytology* / Q000187:drug effects*; D004220:Disulfides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D016106:Methicillin Resistance / Q000187:drug effects*; D008745:Methylation; D050296:Microbial Viability / Q000187:drug effects; D015394:Molecular Structure; D013211:Staphylococcus aureus / Q000166:cytology* / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004220:Disulfides