Ionophore PBT2 as a novel approach to combat antibiotic-resistant Helicobacter pylori

Helicobacter pylori colonizes the gastric mucosa of around half of the world's population and is a major cause of chronic gastritis, peptic ulcer disease, and gastric cancer. Current therapies are becoming increasingly ineffective due to the rapid spread of antibiotic resistance, creating an urgent need for new treatment options with distinct mechanisms of action. Drug repurposing offers a practical and cost-effective approach to address this gap. PBT2 is an 8-hydroxyquinoline derivative originally developed for the treatment of neurodegenerative diseases and has more recently been shown to possess antimicrobial activity. In this study, we demonstrate that PBT2 displays potent bactericidal activity against H. pylori, including multidrug-resistant clinical isolates. PBT2 rapidly killed H. pylori in vitro at low concentrations, with faster killing kinetics than commonly used antibiotics, and no resistance was detected after 30 days of continuous exposure. Importantly, PBT2 was effective in clearing an H. pylori infection in a murine model. Quantitative sequential window acquisition of all theoretical-mass spectrometry proteomic analysis revealed that PBT2 triggers broad disruption of essential bacterial processes, including global suppression of translation, impairment of iron-sulfur cluster assembly and respiration, dysregulation of metal homeostasis, and reduced abundance of virulence- and motility-associated proteins. We reported that PBT2 can act as a nickel ionophore, with Ni²⁺ being the highest-affinity ligand for PBT2 reported to date. Together, these findings suggest that PBT2 acts through a multifaceted, metal-dependent mode of action that limits the potential for emergence of resistance. Our work highlights PBT2 as a promising candidate for repurposing to treat multidrug-resistant H. pylori infections.IMPORTANCEAntibiotic resistance is steadily reducing our ability to treat common bacterial infections, while the development of new antibiotics has slowed. Helicobacter pylori is a clear example of this growing problem, with treatment failures becoming more common worldwide. This study highlights the value of taking a different approach by repurposing existing drugs for new antibacterial uses. Rather than acting on a single bacterial target, the compound examined here disrupts multiple essential processes at once, reducing the probability of resistance developing.