Vm–MSI: a Vancomycin–Antimicrobial Peptide Conjugate Combating Resistant Bacteria and Broadening the Antimicrobial Spectrum

Vancomycin is a critical last-resort treatment for multidrug-resistant Gram-positive bacteria, particularly severe methicillin-resistant S. aureus (MRSA) infections. However, the rise of vancomycin-resistant strains significantly compromises its therapeutic efficacy. To overcome this challenge, recent research has focused on structural modifications of vancomycin using diverse strategies. Herein, the potential of a modification strategy by coupling vancomycin with antimicrobial peptides (AMPs) that have different mechanisms of action is explored. Among the acquired conjugates, Vm-MSI showed a 20.18 fold improvement in antimicrobial activity over vancomycin and a 1.95 fold increase compared to the parent peptide MSI-78. Vm-MSI not only delays the development of resistance in vancomycin-resistant S. aureus (VRSA) but also exhibits potent activity against a wide range of Gram-negative bacteria. Additionally, Vm-MSI demonstrated strong synergy with several conventional antibiotics of distinct mechanisms and displayed potent activities in eradicating biofilms and persisters. Mechanistic studies revealed the complex antibacterial mechanisms of Vm-MSI, which hinder the development of bacterial resistance. In vivo, Vm-MSI displayed remarkable therapeutic efficacy in mouse models of VRSA-induced skin infection and multidrug-resistant A. baumannii-induced lung infection. These findings underscore the great potential of Vm-MSI as an effective treatment for infections caused by vancomycin-resistant and Gram-negative bacteria.