Development of chimeric peptides to facilitate the neutralisation of lipopolysaccharides during bactericidal targeting of multidrug-resistant Escherichia coli

Zhenlong Wang,Jianhua Wang,Xiumin Wang,Ruoyu Mao,Xuehui Liu,Ya Hao,Na Yang,Xiao Wang,Da Teng Da Teng,Zhanzhan Li

doi:10.1038/s42003-020-0761-3

Abstract

Pathogenic Escherichia coli can cause fatal diarrheal diseases in both animals and humans. However, no antibiotics or antimicrobial peptides (AMPs) can adequately kill resistant bacteria and clear bacterial endotoxin, lipopolysaccharide (LPS) which leads to inflammation and sepsis. Here, the LPS-targeted smart chimeric peptides (SCPs)-A6 and G6 are generated by connecting LPS-targeting peptide-LBP14 and killing domain-N6 via different linkers. Rigid and flexible linkers retain the independent biological activities from each component. SCPs-A6 and G6 exert low toxicity and no bacterial resistance, and they more rapidly kill multiple-drug-resistant E. coli and more effectively neutralize LPS toxicity than N6 alone. The SCPs can enhance mouse survival more effectively than N6 or polymyxin B and alleviate lung injuries by blocking mitogen-activated protein kinase and nuclear factor kappa-B p65 activation. These findings uniquely show that SCPs-A6 and G6 may be promising dual-function candidates as improved antibacterial and anti-endotoxin agents to treat bacterial infection and sepsis.

Highlights

Pathogenic Escherichia coli can cause fatal diarrheal diseases in both animals and humans
The nuclear magnetic resonance (NMR) analysis showed that the (EA3K)[2] and G4S linker retained a helical conformation in A6 and random coil in G6 (G15-S19) (Supplementary Fig. 3b, 4, 5 and Table 1)
Diarrheal diseases induced by Gram-negative bacteria such as multidrug resistance (MDR) E. coli remain one of the major severe health threats[1]

Summary

Introduction

Pathogenic Escherichia coli can cause fatal diarrheal diseases in both animals and humans. No antibiotics or antimicrobial peptides (AMPs) can adequately kill resistant bacteria and clear bacterial endotoxin, lipopolysaccharide (LPS) which leads to inflammation and sepsis. The SCPs can enhance mouse survival more effectively than N6 or polymyxin B and alleviate lung injuries by blocking mitogen-activated protein kinase and nuclear factor kappa-B p65 activation These findings uniquely show that SCPs-A6 and G6 may be promising dual-function candidates as improved antibacterial and anti-endotoxin agents to treat bacterial infection and sepsis. GNU7 can enhance selectivity and improve in vitro killing activity against targeted bacteria[13,14,15,16] These studies only provide a basis for the technology in which target-specific CPs were generated against some limited bacterial species, and little attention has been given to their toxicity, resistance, in vivo antibacterial/anti-endotoxic activity. The LBP14 peptide (residues 86–99 of a serum glycoprotein, lipopolysaccharide binding protein (LBP)) can retain significant binding ability to LPS and inhibit the binding of LPS to LBP23,24

Methods

Results

Conclusion