Addressing MRSA infection and antibacterial resistance with peptoid polymers

Jiayang Xie,Jingcheng Zou,Wenjing Zhang,Weinan Jiang,Yuxin Qian,Sheng Chen,Zihao Cong,Runhui Liu,Min Zhou,Minzhang Chen,Longqiang Liu,Zhemin Ji,Ning Shao,Chengzhi Dai,Ximian Xiao,Jin Li

doi:10.1038/s41467-021-26221-y

Abstract

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.

Highlights

Methicillin-Resistant Staphylococcus aureus (MRSA) induced infection calls for antibacterial agents that are not prone to antimicrobial resistance
The optimal peptoid polymer displays superior antibacterial properties: with effective activities against MRSA, persister cell killing, effective eradication of MRSA biofilms, and in vivo antiinfectious effectiveness in a mouse wound model, a mouse keratitis model, and a mouse peritonitis model induced by MRSA (Fig. 1b)
We examined the activity of these poly-Naeg against multiple Gram-positive bacteria, including five strains of MRSA (S. aureus Mu50, S. aureus Newman, S. aureus USA400, S. aureus USA300 LAC, and S. aureus USA300) and three drugsensitive species (S. aureus ATCC6538, S. epidermidis 49134, and B. subtilis BR-151)

Summary

Introduction

Methicillin-Resistant Staphylococcus aureus (MRSA) induced infection calls for antibacterial agents that are not prone to antimicrobial resistance. 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. Peptoids have been explored as antibacterial mimics of HDPs in precedent literatures[42,43,44,45,46,47], but with a very little report for in vivo demonstration[48,49] These HDP mimicking peptoids were mostly prepared from timeconsuming step-by-step solid-phase synthesis[50]. The optimal peptoid polymer displays superior antibacterial properties: with effective activities against MRSA, persister cell killing, effective eradication of MRSA biofilms, and in vivo antiinfectious effectiveness in a mouse wound model, a mouse keratitis model, and a mouse peritonitis model induced by MRSA (Fig. 1b). It is noteworthy that bacteria are unable to acquire resistance against the peptoid polymer owing to the antibacterial mechanism, including the generation of reactive oxygen species (ROS)

Methods

Results

Conclusion