Disulfiram and Copper Ions Kill Mycobacterium tuberculosis in a Synergistic Manner Original paper

What was studied?

This study investigated the synergistic effect of disulfiram, an FDA-approved drug, in combination with copper ions against Mycobacterium tuberculosis (M. tuberculosis). The research aimed to explore how disulfiram and copper, when used together, could enhance the antibacterial properties of copper ions, which are known to play a role in bacterial toxicity. Disulfiram, typically used for alcohol addiction, was tested to determine if it could potentiate copper toxicity against M. tuberculosis, especially considering the challenges posed by drug-resistant strains of tuberculosis.

Who was studied?

The research focused on Mycobacterium tuberculosis, the causative agent of tuberculosis, and Mycobacterium smegmatis, a surrogate organism often used for preliminary studies on tuberculosis. The study used different strains of M. tuberculosis including the wild-type H37Rv strain and a derivative known as mc26230, which is a biosafety-level 2 classified avirulent strain. Both replicating and non-replicating forms of these bacteria were tested under controlled laboratory conditions, including the presence of copper ions and disulfiram.

Most important findings

The study revealed that disulfiram, when combined with copper ions, exhibited strong bactericidal effects on both replicating and non-replicating M. tuberculosis cells. The bactericidal action was significantly more potent when copper was present, highlighting the copper-dependence of disulfiram’s antimicrobial activity. Importantly, the presence of copper enabled the disulfiram-copper complex to bypass the typical copper homeostasis machinery in the bacterial cells, allowing copper to interfere with cellular processes that are usually protected. The researchers observed a copper stress response, indicating that disulfiram facilitates the penetration of copper into the cell, leading to potential cellular damage via interference with iron-sulfur clusters and other copper-sensitive intracellular components. Notably, the disulfiram-copper complex was found to be more effective than copper or disulfiram alone.

Key implications

This study offers a promising new approach to tackling M. tuberculosis, particularly in the context of drug-resistant strains. By enhancing the effectiveness of copper ions with disulfiram, a known medication, this combination could potentially serve as a therapeutic strategy to target M. tuberculosis, including dormant bacterial populations that are typically more challenging to treat with conventional therapies. The findings suggest that repurposing disulfiram could be a viable strategy for treating tuberculosis, particularly in settings where traditional antibiotics are facing resistance. The study also highlights the potential for other small molecules to act synergistically with metal ions to overcome bacterial defenses, paving the way for the development of novel antimicrobial strategies.