Enhancing the Therapeutic Potential of Peptide Antibiotics Using Bacteriophage Mimicry Strategies

The rise of antibiotic resistance, coupled with a declining antibiotic pipeline, poses a substantial threat to global public health. The ESKAPE pathogens-Enterococcus faecium,Staphylococcus aureus,Klebsiella pneumoniae,Acinetobacter baumannii,Pseudomonas aeruginosa, andEnterobacterspecies-have been identified as critical antibiotic-resistant bacteria for which novel therapeutic strategies are desperately needed. Developing new first-in-class antibiotics with novel modes of action remains the most effective approach to combat these resistant pathogens.

Nisin, a ribosomally synthesized and post-translationally modified cationic lanthipeptide, was discovered in 1928, the same year Alexander Fleming identified penicillin. This peptide antibiotic exhibits potent antimicrobial activity against bacterial pathogens, includingEnterococcus faeciumandStaphylococcus aureus, both members of the ESKAPE pathogens. Nisin exerts its bactericidal effects by targeting the pyrophosphate group of lipid II, an essential and conserved moiety, leading to the formation of nisin-lipid II hybrid pores in the bacterial membrane and the inhibition of cell wall synthesis through lipid II sequestration.

Remarkably, no nisin-resistant genes have been reported in foodborne pathogens after more than half a century of its use as a food preservative worldwide, a testament to its novel mode of action. Moreover, nisin's mechanism of action is distinct from that of any clinically used antibiotic, highlighting its potential as an ideal first-in-class candidate for combating antibiotic-resistant pathogens. However, its cationic nature, which leads to hemolysis and cytotoxicity, has impeded its development as a therapeutic antibiotic. Consequently, innovative strategies to transform nisin into a viable intravenous antibiotic are urgently needed.

On November 25^th, 2024, Advanced Science published a novel strategy fortransforming peptide antibiotics into viable therapeutics for combating antibiotic-resistant pathogens. This research was led by Dr. Xinghong Zhao and Dr. Hongping Wan, a team that focuses on Sustainable Antimicrobials research.

In Dr. Zhao and Dr. Wan’s study,nanodelivery systems have been developed by mimicking the mechanisms bacteriophages use to deliver their genomes to host bacteria. These systems utilize bacteriophage receptor-binding proteins conjugated to loading modules, enabling efficient targeting of bacterial pathogens. Peptide antibiotics are loaded via dynamic covalent bonds, allowing for infection microenvironment-responsive payload release. These nanodelivery systems demonstrate remarkable specificity against target pathogens and effectively localize to bacteria-infected lungs invivo. Notably, they significantly reduce the acute toxicity of nisin, rendering it suitable for intravenous administration. Additionally, these bacteriophage-mimicking nanomedicines exhibit excellent therapeutic efficacy in a mouse model of MRSA-induced pneumonia. The facile synthesis, potent antimicrobial performance, and favorable biocompatibility of these nanomedicines highlight their potential as alternative therapeutics for combating antibiotic-resistant pathogens. This study underscores the effectiveness of bacteriophage mimicry as a strategy for transforming peptide antibiotics into viable therapeutics.

This work was supported by the National Key Research and Development Program, the “1000-Talent Program” in Sichuan Province, the Science and Technology Project of Sichuan Province, and the National Natural Science Foundation of China.

For more information, please visit:http://doi.org/10.1002/advs.202411753