Abstract
Antimicrobial peptides (AMPs) are alternative therapeutics to traditional antibiotics against bacterial resistance. Our previous work identified an antimicrobial region at the N-terminus of the eosinophil cationic protein (ECP). Following structure-based analysis, a 30mer peptide (ECPep-L) was designed that combines antimicrobial action against Gram-negative species with lipopolysaccharides (LPS) binding and endotoxin-neutralization activities. Next, analogues that contain non-natural amino acids were designed to increase serum stability. Here, two analogues were selected for in vivo assays: the all-D version (ECPep-D) and the Arg to Orn version that incorporates a D-amino acid at position 2 (ECPep-2D-Orn). The peptide analogues retained high LPS-binding and anti-endotoxin activities. The peptides efficacy was tested in a murine acute infection model of Acinetobacter baumannii. Results highlighted a survival rate above 70% following a 3-day supervision with a single administration of ECPep-D. Moreover, in both ECPep-D and ECPep-2D-Orn peptide-treated groups, clinical symptoms improved significantly and the tissue infection was reduced to equivalent levels to mice treated with colistin, used as a last resort in the clinics. Moreover, treatment drastically reduced serum levels of TNF-α inflammation marker within the first 8 h. The present results support ECP-derived peptides as alternative candidates for the treatment of acute infections caused by Gram-negative bacteria.
Highlights
Publisher’s Note: MDPI stays neutralIt is nearly one century since the landmark discovery of penicillin
Among hundreds of active molecules, we cannot disregard the potential of biomacromolecules such as antimicrobial peptides (AMPs), which are endowed with some unique properties distinct from small molecules, widely used in the drug development field [2,3,4]
The results indicated that when the bacteria were exposed to the peptides at different concentrations below the Minimum Inhibitory Concentration (MIC) value, the growth was altered in a dose-dependent mode
Summary
It is nearly one century since the landmark discovery of penicillin. The emergence of antimicrobial resistance (AMR) is demanding the development of novel antibiotics [1]. Among hundreds of active molecules, we cannot disregard the potential of biomacromolecules such as antimicrobial peptides (AMPs), which are endowed with some unique properties distinct from small molecules, widely used in the drug development field [2,3,4]. AMPs are peptides that can be derived from organisms of all kingdoms and display a variety of functions. AMPs, and in particular cationic AMPs, the most populated group, have common properties and mechanisms because of their physicochemical nature. In with regard to jurisdictional claims in published maps and institutional affiliations
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