Ultrashort cationic lipopeptides (USCLs) are promising alternatives to traditional antibiotics due to their rapid, potent, and broad-spectrum activity, even against multidrug-resistant (MDR) bacteria. Here, we explore how cationic side chain length modulates the antibacterial activity of histidine-based USCLs, using amidated myristoylhistidylhistidine (Myr-HH-NH2) as a template. The middle histidine (His, H) was systematically replaced with arginine (Arg, R), lysine (Lys, K), or its shorter homologues: ornithine (Orn), diaminobutyric acid (Dab), and diaminopropionic acid (Dap) with 3, 2, and 1 methylene units, respectively. Quantum mechanical calculations were performed to assess how this variation in cationic side chain length affects ion pair–π interaction with the membrane lipid palmitoyl oleoylphosphatidylglycerol (POPG). The results suggest that lipopeptides with shorter cationic residues are likely within the optimal window of ion pair–π interactions for potent antibacterial activity. Among the Lys homologues, Orn in Myr-OrnH-NH2 appears to interact optimally, as evidenced by its potent activity against E. coli ATCC 25922 and S. aureus ATCC 25923. In contrast, interactions that are too weak, as with His0 in Myr-HH-NH2, or relatively too strong, as with Lys in Myr-KH-NH2, are associated with reduced activity. Based on these findings, Orn could be the optimal cationic residue with the potential to enhance the antibacterial activity of other His-based peptides. Leveraging these insights, two new temporin-SHf derivatives were designed, with C2K-SHf-1 exhibiting potent activity 250 times that of its parent peptide. Beyond their potential to combat AMR, this study provides valuable insights for the design of next-generation USCLs with superior antimicrobial efficacy.
Salas et al. (Mon,) studied this question.