The Promise of Copper Ionophores as Antimicrobials Original paper

What was reviewed?

This review explains the promise of copper ionophores as antimicrobials and shows how small molecules that shuttle copper into microbes can tip host–pathogen battles. It defines copper-dependent toxicity as a mix of enzyme mismatch and energy failure rather than simple oxidation and maps how ionophores raise intracellular copper above export capacity. It surveys major chemotypes, including 8-hydroxyquinolines, dithiocarbamates such as disulfiram derivatives, pyrithione, and bis-thiosemicarbazones like GTSM and ATSM, and it highlights synergy with standard drugs in resistant strains. The authors link these actions to known host tactics that move copper to infection sites and argue that ionophores can amplify that pressure in vivo. They also discuss delivery designs that lower host toxicity, including pro-ionophores that switch on inside phagolysosomes, and they point to drug repurposing paths from oncology to infectious disease.

Who was reviewed?

The review draws on lab and animal data across priority pathogens and on early clinical insights from related agents. Examples include activity against Mycobacterium tuberculosis, Staphylococcus aureus, including MRSA, Klebsiella pneumoniae, Neisseria gonorrhoeae, Chlamydia trachomatis, and Streptococcus pneumoniae. It cites macrophage models where ionophores boost killing by using host copper, and it includes in vivo work where dithiocarbamates increase lung clearance of pneumococci. It also summarizes transporter genetics that shape entry of copper–ionophore complexes in Escherichia coli, and it reviews how copper efflux loss magnifies ionophore potency. The authors note that several agents, such as PBT2 and bis-thiosemicarbazones, already have human safety data from other fields, which could speed trials for infections.

Most important findings

The review shows that copper ionophores raise free copper inside microbes, which disables iron–sulfur enzymes, stalls nucleotide and carbon use, and collapses respiration on key fuels. Dithiocarbamates drive large rises in intracellular copper and strip the pneumococcal capsule, which tracks with better macrophage clearance and points to a surface shift that matters for biofilms. Pyrithione complexes enter through amino acid and siderophore transporters, which means uptake can be tuned by targeting these routes, and bis-thiosemicarbazones block NADH and succinate dehydrogenases in N. gonorrhoeae, including multidrug-resistant strains. 8-hydroxyquinoline analogs kill M. tuberculosis in a copper-dependent way in vitro and inside macrophages, where host copper supplies the needed metal. Several ionophores sensitize resistant bacteria to old drugs: PBT2 with metals breaks β-lactam resistance in S. pneumoniae and restores aminoglycoside activity in K. pneumoniae.

Key implications

Clinicians can view copper ionophores as tools that amplify host copper pressure while lowering the dose or restoring the effect of standard antibiotics. This approach may help clear drug-resistant Gram-positives, select Gram-negatives, and intracellular pathogens in niches where macrophages already deploy copper. Care must still balance efficacy and host safety; pro-ionophores that activate in phagolysosomes and agents with prior human data offer near-term paths. For microbiome-aware care, track copper stress genes, capsule state, and respiration targets in isolates; these markers explain reduced growth of MRSA, pneumococci, Enterobacterales, N. gonorrhoeae, and C. trachomatis under ionophore pressure. This review supports combined regimens that pair ionophores with β-lactams or aminoglycosides to re-open old drug classes against resistant strains, while calling for trials that define dosing windows, tissue copper effects, and selection risks.