Peptides have important biological functions. However, their susceptibility to proteolysis limits their applications. We demonstrated here for the first time, that poly(2‐oxazoline) (POX) can work as a functional mimic of peptides. POX‐based glycine pseudopeptides, a host defense peptide mimic, had potent activities against methicillin‐resistant S. aureus, which causes formidable infections. The POX mimic showed potent activity against persisters that are highly resistant to antibiotics. S. aureus did not develop resistance to POX owning to the reactive oxygen species related antimicrobial mechanism. POX‐treated S. aureus is sensitive to common antibiotics, demonstrating no observable antimicrobial pressure or cross‐resistance in using antimicrobial POX. This study highlights POX as a new type of functional mimic of peptides and opens new avenues in designing and exploring peptide mimetics for biological functions and applications.

Methicillin-Resistant Staphylococcus aureus (MRSA) induced infection calls for antibacterial agents that are not prone to antimicrobial resistance. We prepare protease-resistant peptoid polymers with variable C-terminal functional groups using a ring-opening polymerization of N-substituted N-carboxyanhydrides (NNCA), which can provide peptoid polymers easily from the one-pot synthesis. We study the optimal polymer that displays effective activity against MRSA planktonic and persister cells, effective eradication of highly antibiotic-resistant MRSA biofilms, and potent anti-infectious performance in vivo using the wound infection model, the mouse keratitis model, and the mouse peritonitis model. Peptoid polymers show insusceptibility to antimicrobial resistance, which is a prominent merit of these antimicrobial agents. The low cost, convenient synthesis and structure diversity of peptoid polymers, the superior antimicrobial performance and therapeutic potential in treating MRSA infection altogether imply great potential of peptoid polymers as promising antibacterial agents in treating MRSA infection and alleviating antibiotic resistance.

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Multidrug-resistant (MDR) bacteria have emerged quickly and have caused serious nosocomial infections. It is urgent to develop novel antimicrobial agents for treating MDR bacterial infections. In this study, we isolated 45 strains of bacteria from hospital patients and found shockingly that most of these strains were MDR to antimicrobial drugs. This inspired us to explore antimicrobial peptide polymers as synthetic mimics of host defense peptides in combating drug-resistant bacteria and the formidable antimicrobial challenge. We found that peptide polymer 80:20 DM:Bu (where DM is a hydrophilic/cationic subunit and Bu is a hydrophobic subunit) displayed fast bacterial killing, broad spectrum, and potent activity against clinically isolated strains of MDR bacteria. Moreover, peptide polymer 80:20 DM:Bu displayed potent in vivo antibacterial efficacy, comparable to the performance of polymyxin B, in a Pseudomonas aeruginosa (P. aeruginosa) infected rat full-thickness wound model. The peptide polymer can be easily synthesized from ring-opening polymerization with remarkable reproducibility in structural properties and biological activities. The peptide polymer’s potent and broad spectrum antimicrobial activities against MDR bacteria in vitro and in vivo, resistance to proteolysis, and high structural diversity altogether imply a great potential of peptide polymer 80:20 DM:Bu in antimicrobial applications as synthetic mimics of host defense peptides.

We design the tetraalkylammonium carboxylate‐initiated superfast polymerization on α‐amino acid N‐carboxyanhydrides (NCA) for efficient synthesis of polypeptides. Carboxylates, as a new class of initiator for NCA polymerization, can initiate the superfast NCA polymerization without the need of extra catalysts and the polymerization can be operated in open vessels at ambient condition without the use of glove box. Tetraalkylammonium carboxylate‐initiated polymerization on NCA easily affords block copolymers with at least 15 blocks. Moreover, this method avoids tedious purification steps and enables direct polymerization on crude NCAs in aqueous environments to prepare polypeptides and one‐pot synthesis of polypeptide nanoparticles. These advantages and the mild polymerization condition of tetraalkylammonium carboxylate‐initiated NCA polymerization imply its great potential in functional exploration and application of polypeptides.