Abstract
Antimicrobial peptides are promising molecules to address the global antibiotic resistance problem, however, optimization to achieve favorable potency and safety is required. Here, a peptide-template modification approach was employed to design physicochemical variants based on net charge, hydrophobicity, enantiomer, and terminal group. All variants of the scorpion venom peptide BmKn-2 with amphipathic α-helical cationic structure exhibited an increased antibacterial potency when evaluated against multidrug-resistant Salmonella isolates at a MIC range of 4–8 µM. They revealed antibiofilm activity in a dose-dependent manner. Sheep red blood cells were used to evaluate hemolytic and cell selectivity properties. Peptide Kn2-5R-NH2, dKn2-5R-NH2, and 2F-Kn2-5R-NH2 (variants with +6 charges carrying amidated C-terminus) showed stronger antibacterial activity than Kn2-5R (a variant with +5 charges bearing free-carboxyl group at C-terminus). Peptide dKn2-5R-NH2 (d-enantiomer) exhibited slightly weaker antibacterial activity with much less hemolytic activity (higher hemolytic concentration 50) than Kn2-5R-NH2 (l-enantiomer). Furthermore, peptide Kn2-5R with the least hydrophobicity had the lowest hemolytic activity and showed the highest specificity to Salmonella (the highest selectivity index). This study also explained the relationship of peptide physicochemical properties and bioactivities that would fulfill and accelerate progress in peptide antibiotic research and development.
Highlights
Antibiotic resistance is one of the most serious problems threatening human health worldwide [1]
The template was modified yielding four physicochemical variants
The variant peptides were determined for their antimicrobial activity, toxicity to sheep red blood cells, and cell selectivity toward Salmonella compared to the sheep RBCs (sRBCs)
Summary
Antibiotic resistance is one of the most serious problems threatening human health worldwide [1]. Antimicrobial peptides (AMPs) have gained considerable attention for developing antibiotics to cope with this crisis They are short amino acid chains exerting antimicrobial activity that may be derived from natural sources produced by various organisms, proteinexcised fragments, and syntheses. More than 3000 AMPs are currently reported and most of them are composed of positively charged and hydrophobic amino acids [3,4] This feature causes them to fold into an amphipathic conformation that plays a vital role in their action without memory or a specific receptor being needed when interacting with biomembranes [5]. They rapidly and simultaneously attack multiple targets, making microbes far less likely to develop resistance compared to conventional antibiotics [4,6]
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