Introduction

The continued emergence and rapid spread of drug-resistant bacteria, coupled with the lack of novel antibiotics, imply the urgent need for new antimicrobial agents. Host defense peptides (HDPs) have been extensively studied as promising drugs against drug-resistant bacterial infections due to their broad-spectrum antimicrobial activity and insusceptibility to drug resistance. However, their application is limited by inherent shortcomings such as low stability upon proteolysis, cumbersome and time-consuming synthesis, and high cost. Therefore, the development of HDP mimetics that are resistant to proteolysis, easy to synthesize, and possess in vivo antimicrobial capability is of great significance.

Methods

The peptoid polymer was tested against drug-resistant Gram-positive bacteria, persister cells, and biofilms. In vitro and in vivo toxicity tests confirmed the high biocompatibility of the polymer. Confocal characterization, ROS test and DNA binding experiment were used to demonstrate the antimicrobial mechanism. Finally, mouse models were used to confirm the in vivo antibacterial efficacy of the peptoid polymer.

Results

In this study, we synthesized a library of antibacterial peptoid polymers with various C-terminal functional groups via one-pot ring-opening polymerization of N-substituted N-carboxyanhydrides (α-NNCAs). The optimal peptoid polymer showed potent activity against methicillin-resistant Staphylococcus aureus (MRSA) planktonic bacteria, persister cells, and biofilm. It’s noteworthy that bacteria are unable to acquire resistance against the peptoid polymer owing to the antibacterial mechanism including the generation of reactive oxygen species and DNA binding. The preferred molecule exhibited effective in vivo anti-infectious performance in the mouse wound model, the mouse keratitis model, and the mouse peritonitis model induced by MRSA. In addition, the polymer also displayed potent in vitro and in vivo antibacterial activity against various other drug-resistant Gram-positive bacteria.

Conclusion

This study demonstrates the potential of peptoid polymers mimicking HDP in the treatment of drug-resistant microbial infections, mitigation of antibiotic resistance and development of antibacterial materials.