Cyclometalated Iridium(III) Complexes with eDNA-Degrading Activity for Combating Gram-Positive Bacterial Biofilms

Biofilm-associated infections pose a significant clinical challenge due to the high resistance of bacteria within biofilms to conventional antibiotics. Extracellular DNA (eDNA) is a key structural component that facilitates bacterial adhesion and biofilm development. Metal complexes that target eDNA represent a promising strategy to disrupt biofilm integrity and eliminate biofilm-protected bacteria. In this study, four cyclometalated iridium complexes (Ir1-4) were rationally designed and synthesized, which selectively targeted Gram-positive bacteria through interactions with lipoteichoic acids (LTA) in their cell walls. Among them, Ir2, with chlorine atoms in the meta position, demonstrated superior antimicrobial activity. Ir2 efficiently killed bacteria by damaging the bacterial membrane and degrading genomic DNA. Additionally, Ir2 penetrated biofilms and disrupted them by degrading eDNA, thereby facilitating the eradication of resident bacteria. Metabolomics analysis revealed that Ir2 induced bacterial metabolic dysregulation, including inhibition of amino acid synthesis, obstruction of ABC transport, and elevation of DNA damage. In vivo experiments confirmed that topical application of Ir2 significantly suppressed Staphylococcus aureus (S. aureus) biofilm-infected wounds in murine models, promoting wound healing. This work provides a promising platform for developing antimicrobials focused on the targeting of eDNA to eliminate biofilm-associated infections.