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It is traditionally believed that the distribution of tryptophan (Trp) residues is critical for the novo design of antimicrobial peptides (AMPs). However, there is scarce knowledge regarding Trp residues arrangement at the head group level. Thus, a set of α‐helical AMPs containing different Trp residue arrangements at the N‐/C‐terminal of sequence were designed to increase the strategy database and analyze their biological activities. The arrangement of the N‐terminal Trp residue significantly improved the bacteriostatic activity of the peptides, but the C‐terminal Trp residue arrangement reduced the biocompatibility of them. WL and LW were effective against Gram‐negative microbes and had high selectivity for bacteria as compared to human erythrocytes and mammalian cells. They both maintained a relatively desirable activity in the presence of physiological salts and serum. It is observed through electron microscope, flow cytometry and fluorescence spectroscopy that target peptides can penetrate bacterial cell membrane and kill it by damaging cell membrane integrity. Collectively, we determined the structure–activity relationship of Trp residue distributions in a symmetric sequence structure and filled the gap in knowledge related to Trp arrangements at the head group level. The obtained results will be helpful in designing of artificial peptide‐based antimicrobials. [ABSTRACT FROM AUTHOR]

High manufacturing costs and weak cell selectivity have limited the clinical application of naturally occurring peptides when faced with an outbreak of drug resistance. To overcome these limitations, a set of antimicrobial peptides was synthesized with the general sequence of (WL)n, where n = 1, 2, 3, and WL was truncated from the N‐terminus of Cecropin P1 without initial serine residues. The antimicrobial peptide WL3 exhibited stronger antimicrobial activity against both Gram‐negative and Gram‐positive microbes than the parental peptide CP‐1. WL3 showed no hemolysis even at the highest test concentrations compared to the parental peptide CP‐1. The condition sensitivity assays (salts, serum, and trypsin) demonstrated that WL3 had high stability in vitro. Fluorescence spectroscopy and electron microscopy indicated that WL3 killed microbes by means of penetrating the membrane and causing cell lysis. In a mouse model, WL3 was able to significantly reduce the bacteria load in major organs and cytokines (TNF‐α, IL‐6, and IL‐1β) levels in serum. In summary, these findings suggest that WL3, which was modified from a natural antimicrobial peptide, has enormous potential for application as a novel antibacterial agent. [ABSTRACT FROM AUTHOR]

Our previous study reported Val/Arg-rich peptides, and the relationship was linear between hydrophobicity and antimicrobial potency within a certain range. Here, we further develop a new series of analogs to investigate the effect of net charge and Pro residue on activity. Replacement of Gly with Ala or Pro led to the decrease in antimicrobial activity. The substitution of Gly with Ala retained its hemolytic activity, while the substitution with Pro significantly decreased the toxicity, suggesting positive effect of Pro on hemolytic activity. The increase in net charge from +4 to +6 significantly improved antimicrobial activity and decreased the hemolysis. However, antibacterial and hemolytic activities were not affected by increasing the net charge from +6 to +8, indicating a moderate net positive charge. The peptides produced larger blue shifts in PE/ PG than in PC/cholesterol, suggesting a stronger affinity with negatively charged membrane over zwitterionic membrane. Lowering the net charge or insert of Pro led to the lack of α-helical structure in SDS micelles, which may be correlated with weakened antimicrobial potency. This study indicated that Val/Arg-rich peptides should have moderate net charge and Pro may play a role in reducing the toxicity against red blood cells. [ABSTRACT FROM AUTHOR]