Cyclic dipeptide-based antimicrobials with potent antibacterial activity

The spread of antibiotic resistance has become a major challenge in global public health, and there is an urgent need to develop novel antibacterial agents with low resistance. Peptide-based antibacterial agents have attracted increasing attention for their membrane-targeting mechanisms, which may reduce the risk of the development of resistance. Herein, a series of quaternary ammonium-modified cyclic dipeptides (named cHHn-m) were designed and synthesized through a quaternization reaction and their antibacterial activity and cytotoxicity were systematically investigated. The optimal cyclic dipeptides (cHH8-6) demonstrated the best antibacterial ability with MIC values of 2.0 and 3.9 μg mL^-1 against S. aureus and E. coli, respectively. Antibacterial mechanism studies indicate that cHH8-6 can bind to a negatively charged bacterial membrane through electrostatic interactions, subsequently disrupting the integrity of the bacterial membrane. Due to its unique mechanism, cHH8-6 is less likely to induce bacterial resistance compared to clinical antibiotics. In addition, cHH8-6 effectively inhibited bacterial biofilm formation and eradicated mature bacterial biofilms. In bacterial-induced mouse models of epidermal and keratitis infections, cHH8-6 effectively reduces the bacterial count at the infection site with negligible in vivo toxicity. This study provides a novel approach for treating clinical bacterial infections.