Designed Hexadecapeptides Synergize Glycopeptide Antibiotics Vancomycin and Teicoplanin against Pathogenic via Disruption of Cell Permeability and Potential.

Given the worldwide prevalence of pathogenic drug-resistant bacteria and the slow pace of new antibacterial development, discovering new uses for approved drugs that are outside the scope of the original indication is increasingly becoming an attractive proposition. In this work, seven linear cationic hexadecapeptides were designed, synthesized, and characterized. These amphiphilic peptides are able to transform from the random coil structure in water to α-helix in SDS solution and have only modest bioactivity to limited bacterial strains when used alone. Surprisingly, one of them, namely, , was found to demonstrate significant synergy with vancomycin and teicoplanin against highly pathogenic () with FIC index as low as 0.03. Checkerboard assay indicated that, in the presence of 8 μM , the minimum inhibitory concentration (MIC) of vancomycin greatly was reduced from >128 to 1 μM to clinically isolated carbapenem-resistant . Additionally, the vancomycin- combination exhibited neglectable toxicity and . Further efficacy studies confirmed that the survival rate of a combination therapy at 100 mg/kg of and vancomycin was 30% higher than that of the single-drug treatment. More importantly, drug resistance has not developed to the combination even at the 20th serial passage of . Mechanistic studies revealed that could strengthen the vancomycin's influence on cell permeability and potential, leading to markedly reduced biofilm formation and rapid bactericidal effect. This new combination strategy expands the antibacterial spectrum of glycopeptide antibiotics and opens a new research direction for their application to treat pathogenic infection.