Abstract
In an effort to provide new treatments for the global crisis of bacterial resistance to current antibiotics, we have used a rational approach to design several new antimicrobial peptides (AMPs). The present study focuses on 24-mer WLBU2 and its derivative, D8, with the amino acid sequence, RRWVRRVRRWVRRVVRVVRRWVRR. In D8, all of the valines are the d-enantiomer. We use X-ray low- and wide-angle diffuse scattering data to measure elasticity and lipid chain order. We show a good correlation between in vitro bacterial killing efficiency and both bending and chain order behavior in bacterial lipid membrane mimics; our results suggest that AMP-triggered domain formation could be the mechanism of bacterial killing in both Gram-positive and Gram-negative bacteria. In red blood cell lipid mimics, D8 stiffens and orders the membrane, while WLBU2 softens and disorders it, which correlate with D8's harmless vs. WLBU2's toxic behavior in hemolysis tests. These results suggest that elasticity and chain order behavior can be used to predict mechanisms of bactericidal action and toxicity of new AMPs.
Highlights
The world is facing a growing threat from bacteria that are resistant to available antibiotics.[1,2] Several strategies are being utilized to combat this threat, including eliminating antibiotics from animal feed, increasing antibiotic stewardship, reducing transmission in hospital settings and designing new types of antibiotics
In our previous study of the antimicrobial peptides (AMPs) colistin interacting with membrane mimics,[44] we found a correlation between irregular elasticity and chain order in G(−) inner membrane G(−) (IM) mimics and killing of G(−) bacteria, which we interpreted as domain formation
In this work we show similar elastic behavior of WLBU2 and D8 with the G(−) IM and G(+) bacterial membrane mimics that increase stiffness and chain order at low concentrations, and soften and disorder these membranes at higher concentrations
Summary
The world is facing a growing threat from bacteria that are resistant to available antibiotics.[1,2] Several strategies are being utilized to combat this threat, including eliminating antibiotics from animal feed, increasing antibiotic stewardship, reducing transmission in hospital settings and designing new types of antibiotics. Most current classes of antibiotics inhibit a specific metabolic pathway and typically require multiple doses to eradicate bacterial infections, during which time a resistance phenotype can occur.[3] As a result, a class of pathogens termed ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) has been identified as the most common multidrug-resistant (MDR) bacteria.[4] As a component of the host innate immune system, natural antimicrobial peptides[5] (AMPs) such as human cathelicidin LL-376 have inspired the rational design of novel synthetic AMPs. Some of us have developed new AMPs that were inspired by both natural AMPs and the lytic peptide, LLP1, part of the C-terminus of the HIV-1 gp[41] fusion protein.[7] These peptides contain a cationic amphipathic motif with only 2 or 3 types of amino acids compared to natural peptides. Some of us previously demonstrated that WLBU2 was more effective than LL37 (made of 14 different types of amino acids) in animal models.[9,10,11] In a recent study, it was demonstrated that WLBU2 is able to overcome resistance from 92% of 142 clinical isolates representing the ESKAPE pathogens, including those resistant to colistin and LL-37.12 In addition, WLBU2 effectively treated a variety of clinical methicillin-resistant S. aureus surgical implant biofilms.[13]
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