Blood Compatibility-An Important but Often Forgotten Aspect of the Characterization of Antimicrobial Peptides for Clinical Application.

Ute Fichtinger,Jens Hartmann,Jennifer Zottl,Karl Lohner,Claudia Schildböck,Stephan Harm

doi:10.3390/ijms20215426

Abstract

Acylation of antimicrobial peptides mimics the structure of the natural lipopeptide polymyxin B, and increases antimicrobial and endotoxin-neutralizing activities. In this study, the antimicrobial properties of lactoferrin-based LF11 peptides as well as blood compatibility as a function of acyl chain length were investigated. Beyond the classical hemolysis test, the biocompatibility was determined with human leukocytes and platelets, and the influence of antimicrobial peptides (AMPs) on the plasmatic coagulation and the complement system was investigated. The results of this study show that the acylation of cationic peptides significantly reduces blood tolerance. With increasing acyl chain length, the cytotoxicity of LF11 peptides to human blood cells also increased. This study also shows that acylated cationic antimicrobial peptides are inactivated by the presence of heparin. In addition, it could be shown that the immobilization of LF11 peptides leads to a loss of their antimicrobial properties.

Highlights

In recent years, multidrug resistance (MDR) of bacteria has become a global health problem, and there is an increasing demand for new antimicrobial agents and antibiotics
This led to increased antimicrobial activity against Escherichia coli, which correlates with the degree of permeability of bacterial membranes of these peptides [3,4]
It has been shown recently that Toraymyxin acts as a delivery system of Polymyxin B (PMB) by releasing the non-covalently bound fraction into the patients’ blood stream, and LPS is neutralized by PMB, which results in a prevention of the activation of pattern recognition receptors

Summary

Introduction

Multidrug resistance (MDR) of bacteria has become a global health problem, and there is an increasing demand for new antimicrobial agents and antibiotics. In order to improve the antimicrobial activity of some AMPs, their hydrophobic properties were increased by targeted N-acylation This led to increased antimicrobial activity against Escherichia coli, which correlates with the degree of permeability of bacterial membranes of these peptides [3,4]. Some AMPs have a high affinity to lipopolysaccharides (LPS, endotoxins) from Gram-negative bacteria and are able to suppress an LPS-induced release of tumor necrosis factor alpha (TNF-α) and could protect mice from lethal endotoxemia [3,4]. Among these is Polymyxin B (PMB), a naturally occurring AMP produced by Bacillus polymyxa. There is currently no membrane/adsorption based blood purification system available that is able to remove LPS from the patients’ blood

Methods

Results

Conclusion