C-Terminal Modification Contributes the Antibacterial Activity of a Cecropin-like Region of Heteroscorpine-1 from Scorpion Venom

The rise of multidrug-resistant pathogens has become a serious health concern, creating an urgent need for novel therapeutic approaches. Among the compounds explored, AMPs have emerged as promising candidates due to their broad-spectrum activity and low propensity for resistance development. However, their clinical implementation is limited by improper size, in vivo instability, and toxicity. Here, we designed short analogs of CeHS-1 via (1) truncation of intact CeHS-1, (2) amino acid substitution, (3) end-tagging, and (4) C-terminal amidation. The results showed that short analogs fused with an RWW stretch exhibited stronger antibacterial activity than the parent analogs, without inducing hemolysis in human red blood cells. Among the tested AMPs, mechanistic studies revealed membrane-disruptive activity of certain peptides against Staphylococcus aureus. In silico analyses also suggested that the analogs bind DNA by aligning parallel to its grooves, where the RWW stretch is believed to contribute to interactions between arginine and tryptophan residues and nitrogenous bases through electrostatic, hydrogen bonding, and hydrophobic interactions. The short CeHS-1 analogs established here may serve as potential alternative antimicrobial agents, which should be tested in clinical trials in the future.