Postmodification of Daptomycin at Tryptophan Enables the Discovery of Aryl-Daptomycin Antibiofilm Activity against MRSA

Abstract Biofilm-related infections pose a growing global health threat and demand novel therapeutic agents. Although Daptomycin is effective against Gram-positive bacteria and biofilms, the emergence of resistant strains necessitates next-generation derivatives. Herein, a library of aryl-Daptomycin was successfully constructed by postmodification of Daptomycin at the tryptophan residue. The lead compound 1i exhibited improved antibacterial activity, antibiofilm efficacy, and stability compared with Daptomycin, and also showed rapid killing of both planktonic and persister cells. In vivo studies, 1i significantly reduced drug-resistant bacterial counts and biofilm burdens in mouse models of skin wound infection and catheter-related biofilm infection. Mechanistic studies revealed that it exerts antibacterial activity by inducing membrane depolarization and disruption, while it inhibits biofilm formation by downregulating the ica gene and blocking the agr system. Moreover, molecular dynamics simulations confirmed the higher tetrameric stability of 1i compared with Daptomycin. Collectively, 1i represents a promising candidate for clinical treatment of bacterial infections.