Coupling a Virulence-Targeting Moiety with Ru-Based AMP Mimics Efficiently Improved Its Anti-Infective Potency and Therapeutic Index.

The surge of antibiotic resistance in calls for novel drugs that attack new targets. Developing antimicrobial peptides (AMPs) or antivirulence agents (AvAs) is a promising strategy to tackle this challenge. However, AMPs, which kill bacteria by disrupting cell membranes, suffer from low stability and high synthesis cost, while AvAs, which inhibit toxin secretion, have relatively poor bactericidal activity. Here, to address their respective shortcomings, we combined these two different antibacterial activities on the same molecular scaffold and developed a Ru-based metalloantibiotic, termed . Notably, exerted remarkable bactericidal activity (MIC = 460 nM) and attenuated bacterial virulence as well. Mechanistic studies demonstrated that had two independent targets: CcpA and bacterial membrane integrity. Based on its dual mechanism of action, effectively overcame resistance and showed high efficacy in a mouse infection model against . This study provides a promising approach to confronting bacterial infections.