Antibiotics 2025, 14(8), 784; https://doi.org/10.3390/antibiotics14080784 (registering DOI) - 1 Aug 2025
Abstract
Background/Objectives: The clinical potential of antimicrobial peptides (AMPs) against dual threats like antimicrobial resistance (AMR) and cancer is often limited by their high host cell toxicity. Here, we focused on brevinin-2OS (B2OS), a novel peptide from the skin of Odorrana schmackeri with
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Background/Objectives: The clinical potential of antimicrobial peptides (AMPs) against dual threats like antimicrobial resistance (AMR) and cancer is often limited by their high host cell toxicity. Here, we focused on brevinin-2OS (B2OS), a novel peptide from the skin of Odorrana schmackeri with potent haemolytic activity. The objective was to study the structure–activity relationship and optimise the safety via targeted modifications. Methods: A dual-modification strategy involving C-terminal truncation and subsequent N-terminal D-amino acid substitution was employed. The bioactivities and safety profiles of the resulting analogues were evaluated using antimicrobial, haemolysis, and cytotoxicity assays. Result: Removal of the rana box in B2OS(1-22)-NH2 substantially reduced haemolysis while maintaining bioactivities. Remarkably, the D-leucine substitution in [D-Leu2]B2OS(1-22)-NH2 displayed a superior HC50 value of 118.1 µM, representing a more than ten-fold improvement compared to its parent peptide (HC50 of 10.44 µM). This optimised analogue also demonstrated faster bactericidal kinetics and enhanced membrane permeabilisation, leading to a greater than 22-fold improvement in its therapeutic index against Gram-positive bacteria. Conclusions: The C-terminal rana box is a primary determinant of toxicity rather than a requirement for activity in the B2OS scaffold. The engineered peptide [D-Leu2]B2OS(1-22)-NH2 emerges as a promising lead compound, and this dual-modification strategy provides a powerful design principle for developing safer, more effective peptide-based therapeutics.
Full article
(This article belongs to the Section Antimicrobial Peptides)
