Sixteen disulfides derived from disulfiram (Antabuse™) were evaluated as antibacterial agents. Derivatives with hydrocarbon chains of seven and eight carbons in length exhibited antibacterial activity against Gram-positive Staphylococcus, Streptococcus, Enterococcus, Bacillus, and Listeria spp. A comparison of the cytotoxicity and microsomal stability with disulfiram further revealed that the eight carbon chain analog was of lower toxicity to human hepatocytes and has a longer metabolic half-life. In the final analysis, this investigation concluded that the S-octylthio derivative is a more effective growth inhibitor of Gram-positive bacteria than disulfiram and exhibits more favorable cytotoxic and metabolic parameters over disulfiram.
Anti-Bacterial Agents/pharmacology , Disulfiram/analogs & derivatives , Disulfiram/pharmacology , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/toxicity , Ciprofloxacin/pharmacology , Disulfiram/chemical synthesis , Disulfiram/toxicity , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Half-Life , Hep G2 Cells , Humans , Microbial Sensitivity Tests , Microsomes, Liver/drug effects , Molecular Structure , Rats , Vancomycin/pharmacology
A chemical library comprised of nineteen synthesized pyridyl disulfides that emulate the chemical reactivity of allicin (garlic) was evaluated for antimicrobial activity against a panel of pathogenic bacteria. Gram-positive species including vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus (VISA, VRSA) demonstrated the highest level of susceptibility toward analogs with S-alkyl chains of 7-9 carbons in length. Further biological studies revealed that the disulfides display synergy with vancomycin against VRSA, cause dispersal of S. aureus biofilms, exhibit low cytotoxicity, and decelerate S. aureus metabolism. In final analysis, pyridyl disulfides represent a novel class of mechanism-based antibacterial agents that have a potential application as antibiotic adjuvants in combination therapy of S. aureus infections with reduced vancomycin susceptibility.
Anti-Bacterial Agents/pharmacology , Disulfides/pharmacology , Methicillin-Resistant Staphylococcus aureus/drug effects , Pyridines/pharmacology , Sulfinic Acids/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Biofilms/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Disulfides/chemistry , Dose-Response Relationship, Drug , Humans , Methicillin-Resistant Staphylococcus aureus/growth & development , Microbial Sensitivity Tests , Molecular Structure , Pyridines/chemistry , Structure-Activity Relationship , Sulfinic Acids/chemistry
Thiolated fluoroquinolones were synthesized from ciprofloxacin and evaluated for antimicrobial activity against a panel of pathogenic bacteria. Gram-positive species including methicillin-resistant Staphylococcus aureus (MRSA) exhibited the highest level of increased sensitivity toward ciprofloxacin bound with a N-propylthio substituent. Evidence was found that the antibiotics form disulfides with low molecular weight thiols in bacteria and potentiate generation of cytosolic reactive oxygen species (ROS). In final analysis, the enhanced anti-MRSA activity of thiolated fluoroquinolones was attributed to increased cell permeability and reaction with cytosolic thiols that yields an inactive disulfide metabolite and the parent drug ciprofloxacin as an inhibitor of DNA synthesis.
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Fluoroquinolones/chemistry , Fluoroquinolones/pharmacology , Sulfinic Acids/chemistry , Sulfinic Acids/pharmacology , Bacterial Infections/drug therapy , Disulfides , Humans , Methicillin-Resistant Staphylococcus aureus/drug effects , Sulfhydryl Compounds/chemistry , Sulfhydryl Compounds/pharmacology
