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

Disulfide analogs of the alcohol sobriety medication disulfiram (Antabuse(™)) were evaluated for antimicrobial activity. Structure-activity relationship analyses of MIC data obtained for 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 MRSA to the bactericidal effects of fosfomycin. Mechanistic studies established that the compounds decrease intracellular levels of the fosB cofactor bacillithiol through a thiol-disulfide exchange reaction. The altered MRSA susceptibility was thereby attributed to a depleted cellular bacillithiol pool available for fosB inactivation of fosfomycin.