Repurposing disulfiram for treatment of Staphylococcus aureus infections.

Abstract

BACKGROUND:

Antimicrobial resistance is an urgent threat affecting healthcare systems worldwide. Identification of novel molecules capable of escaping current resistance mechanisms and exhibiting potent activity against highly drug-resistant strains is the unmet need of the hour.

METHODS:

Whole cell growth inhibition assays were used to screen and identify novel inhibitors. The hit compounds were tested against Vero cells to determine the selectivity index, followed by time-kill kinetics against Staphylococcus aureus. The ability of disulfiram to synergize with several approved drugs utilized for the treatment of S. aureus was determined using fractional inhibitory concentration indexes, followed by its ability to decimate staphyloccocal infections ex vivo. Finally, the in-vivo potential of disulfiram was determined in a neutropenic murine model of S. aureus infection.

RESULTS:

The screening showed that disulfiram has equipotent antibacterial activity against S. aureus, including clinical drug-resistant strains (minimum inhibitory concentration 8-16 mg/L). Disulfiram exhibited concentration-dependent bactericidal activity (∼7 log10 colony-forming units/mL reduction), synergized with linezolid and gentamycin against S. aureus, eradicated staphylococcal biofilms (64-fold better than vancomycin), decimated intracellular S. aureus better than vancomycin, exhibited longer post antibiotic effect than vancomycin, and reduced bacterial counts in murine thigh as well as vancomycin at 50 mg/kg.

CONCLUSION:

Taken together, disulfiram exhibits all the characteristics required for repurposing as an antibacterial targeting staphylococcal infections.

• Authors: Ritesh Thakare, Manjulika Shukla, Grace Kaul, Arunava Dasgupta, Sidharth Chopra
• Journal: International journal of antimicrobial agents (Int J Antimicrob Agents) Vol. 53 Issue 6 Pg. 709-715 (Jun 2019) ISSN: 1872-7913 [Electronic] Netherlands
• PMID: 30954635 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Chemical References

• Alcohol Deterrents
• Anti-Bacterial Agents
• Disulfiram

Topics

• Alcohol Deterrents (pharmacology, therapeutic use)
• Animals
• Anti-Bacterial Agents (pharmacology, therapeutic use)
• Chlorocebus aethiops
• Disease Models, Animal
• Disulfiram (pharmacology, therapeutic use)
• Drug Evaluation, Preclinical
• Mice, Inbred BALB C
• Microbial Sensitivity Tests
• Staphylococcal Infections (drug therapy, microbiology)
• Staphylococcus aureus (drug effects)
• Therapeutic Index, Drug
• Treatment Outcome
• Vero Cells