Repurposing Ionophores to Tackle Antimicrobial Resistance with a Focus on PBT2

Antimicrobial resistance (AMR) remains a growing global health challenge. While resistant bacterial strains continue to emerge and spread, the development of new antibiotics has remained slow. This gap has increased interest in drug repurposing as a promising strategy to combat multidrug-resistant (MDR) pathogens. Ionophores are a structurally diverse group of natural and synthetic compounds that transport ions across biological membranes. Many ionophores were originally developed and widely used for the prevention and treatment of coccidiosis, a common protozoan parasitic intestinal disease in poultry and livestock. Recent studies suggest that some ionophores inhibit bacterial growth directly or enhance the activity of existing antibiotics by perturbing bacterial metal homeostasis, inducing oxidative stress, disturbing membrane function and disrupting biofilms. Among these compounds, PBT2, an 8-hydroxyquinoline derivative with zinc/copper ionophore activity, is an important example. PBT2 acts principally as an antibiotic adjuvant, restoring the activity of conventional antibiotics against several MDR pathogens when combined with zinc. PBT2 also demonstrates narrow-spectrum bactericidal activity as a monotherapy against selected Gram-negative bacteria, including Neisseria gonorrhoeae, Neisseria meningitidis and Helicobacter pylori. PBT2 has prior human exposure from Phase II trials in neurodegenerative diseases, but its antibacterial pharmacokinetics and pharmacodynamics remain undefined. This review summarises the discovery, classification and repurposing of ionophores, and examines the antibacterial activities of PBT2 and its proposed mechanisms of action. Finally, we discuss the translational barriers to the clinical use of ionophores, including bacterial selectivity, resistance risk, toxicity and safety.