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

The Journal of Antibiotics volume 75, pages 146–154 (2022)Cite this article

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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 exchange reaction. The increased fosfomycin susceptibility in S. aureus was thereby attributed to a depleted cellular bacillithiol pool available for inactivation by fosB.

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Acknowledgements

This work was supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health under award number AI151970. Test organisms (Table 1S) were acquired from the American Type Culture Collection, FDA-CDC Antimicrobial Resistance Isolate Bank, and the Network on Antimicrobial Resistance in Staphylococcus aureus (NARSA) for distribution by BEI Resources, NIAID, and NIH.

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  1. These authors contributed equally: Alexandria D. Lewis, Taylor M. Riedel

Authors and Affiliations

  1. Department of Pharmaceutical Science and Research, School of Pharmacy, Marshall University, Huntington, WV, USA

    Alexandria D. Lewis, Taylor M. Riedel, Meredith B. A. Kesler, Melinda E. Varney & Timothy E. Long

  2. Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA

    Timothy E. Long

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Correspondence to Timothy E. Long.

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Lewis, A.D., Riedel, T.M., Kesler, M.B.A. et al. Pharmacological evaluation of disulfiram analogs as antimicrobial agents and their application as inhibitors of fosB-mediated fosfomycin resistance. J Antibiot 75, 146–154 (2022). https://doi.org/10.1038/s41429-022-00500-2

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