Alpha-beta chimeric polypeptide molecular brushes display potent activity against superbugs-methicillin resistant Staphylococcus aureus

Staphylococcus aureus(S.aureus)are frequently encountered for both nosocomial infections and community acquired infections,with special concerns on the quick emergence of methicillin resistant S.aureus(MRSA)[1,2].Antibiotics are used extensively to treat these infections[2].However,antimicrobial resistance has been a tremendous challenge against current antibiotic and calls for urgent actions to explore novel antimicrobial agents that are active against MRSA and are less susceptible to antimicrobial resistance than do conventional antibiotics[3–13].Encouraged by the low propensity for microbes to develop antimicrobial resistance,host defense peptides(HDPs)and their synthetic mimics were actively studied[3,4,14–34].Although peptidyl mimics of HDP have variable structures,many of them involved multiple copies ofα-L-lysine to introduce into the molecules positive charges that were critical for the antimicrobial activity[35,36].

Breaking or following the membrane-targeting mechanism:Exploring the antibacterial mechanism of host defense peptide mimicking poly(2-oxazoline)s

Peptides exert important biological functions but their application is hindered by their susceptibility to proteolysis and poor stability in vivo.Thus,functional peptide mimics have drawn a great deal of attention to address this challenge.Poly(2-oxazoline)s,a class of biocompatible and proteolysis-resistant polymer,can work as host defense peptide mimics without following the general membrane-targeting mechanism as shown in our previous work.This observation encouraged us to figure out if poly(2-oxazoline)s are special and break the general membrane-targeting mechanism of host defense peptides and their mimics.In this study,we aimed at the connection between structure and antibacterial mechanism of poly(2-oxazoline)s.A new γ-aminobutyric acid(GABA)-pendent poly(2-oxazoline)was synthesized and investigated to compare with glycine-pendent poly(2-oxazoline)in our previous study,with the former polymer has two extra CH2 groups in the sidechain to increase the hydrophobicity and amphiphilicity.Membrane depolarization assay suggested that incorporating two more CH2 groups into the sidechain of poly(2-oxazoline)resulted in a mechanism switch from DNA-targeting to membrane-targeting,which was supported by the slow time-kill kinetics and slightly distorted and sunken membrane morphology.Besides,GABA-pendent poly(2-oxazoline)showed potent activity against methicillin-resistant S.aureus and low hemolysis on human red blood cells.Moreover,repeated use of the antimicrobial poly(2-oxazoline)did not stimulate bacteria to obtain resistance,which was an obvious advantage of membrane-targeting antimicrobial agents.