Disulfiram-based disulfides as narrow-spectrum antibacterial agents

Bioorg Med Chem Lett. 2018 May 1;28(8):1298-1302. doi: 10.1016/j.bmcl.2018.03.023.

Jordan G Sheppard ¹, Keely R Frazier ¹, Pushkar Saralkar ², Mohammad F Hossain ¹, Werner J Geldenhuys ², Timothy E Long ³

Affiliations

1 Department of Pharmaceutical Science and Research, School of Pharmacy, Marshall University, Huntington, WV, USA.
2 Department of Pharmaceutical Science, School of Pharmacy, West Virginia University, Morgantown, WV, USA.
3 Department of Pharmaceutical Science and Research, School of Pharmacy, Marshall University, Huntington, WV, USA; Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA. Electronic address: longt@marshall.edu.

PMID: 29571571 DOI: 10.1016/j.bmcl.2018.03.023

Abstract

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.

Keywords

Antibiotic; Disulfides; Disulfiram; MRSA; Staphylococcus; VISA; VRSA.

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