Pyridine-containing iridium complexes as gram-negative bacteria specific therapeutic agents with low resistance development

The propensity of antibiotics to provoke drug resistance in clinical applications, along with their low selectivity, has collectively contributed to the problem of antibiotic misuse, posing a major challenge in contemporary antibacterial therapy. To tackle this issue, we designed and synthesized three amphiphilic pyridine-modified iridium complexes [Ir(ppy)₂(bpy-Py)]⁺Cl⁻(IrP), [Ir(dFppy)₂(bpy-Py)]⁺Cl⁻(IrF) and [Ir(dpqx)₂(bpy-Py)]⁺Cl⁻(Ir-X). All three complexes exhibited stronger bactericidal activity against Gram-negative E. coli, P. aeruginosa and A.baumannii than against Gram-positive S. aureus and E. faecalis. These three complexes selectively bound to Gram-negative pathogens over Gram-positive pathogens. Among them, Ir-X with increased lipophilicity (logP = 2.58) exhibited the most promising profile, and superior antibacterial efficacy. Mechanistic studies revealed that Ir-X combats E. coli through membrane disruption, ROS generation, and ATP depletion, collectively leading to bacterial death. In vivo experiments in a murine model of acute peritonitis demonstrated that Ir-X effectively suppresses E. coli infection without causing significant tissue damage, highlighting its potential as a therapeutic agent for treating Gram-negative bacterial infections.