Pharmacological evaluation of disulfiram analogs as antimicrobial agents and their application as inhibitors of fosB-mediated fosfomycin resistance.

ABSTRACT: Disulfide analogs of the alcohol sobriety medication disulfiram (Antabuse®) were evaluated for antimicrobial activity. Structure-activity relationship analyses of MIC data obtained for methicillin-resistant Staphylococcus aureus (MRSA) and other pathogenic organisms revealed correlations between the lipophilicity and bulkiness of the substituents. Analogs conferring optimal anti-MRSA activity contained S-octyl disulfides and either N,N-dimethyl- or N-pyrrolidine dithiocarbamate substituents. Additional testing revealed that both disulfiram and its S-octyl derivative are capable of sensitizing S. aureus to the bactericidal effects of fosfomycin. Mechanistic studies established that the compounds decrease intracellular levels of the fosB cofactor bacillithiol through a thiol-disulfide exchan

SUBMITTER: Lewis AD 

PROVIDER: S-EPMC8852335 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature