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 (<b>Ir1-4</b>) were rationally designed and synthesized, which selectively targeted Gram-positive bacteria through interactions with lipoteichoic acids (LTA) in their cell walls. Among them, <b>Ir2</b>, with chlorine atoms in the <i>meta</i> position, demonstrated superior antimicrobial activity. <b>Ir2</b> efficiently killed bacteria by damaging the bacterial membrane and degrading genomic DNA. Additionally, <b>Ir2</b> penetrated biofilms and disrupted them by degrading eDNA, thereby facilitating the eradication of resident bacteria. Metabolomics analysis revealed that <b>Ir2</b> induced bacterial metabolic dysregulation, including inhibition of amino acid synthesis, obstruction of ABC transport, and elevation of DNA damage. <i>In vivo</i> experiments confirmed that topical application of <b>Ir2</b> significantly suppressed <i>Staphylococcus aureus</i> (<i>S. aureus</i>) 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.