Structural determinants of the scorpion venom peptide Uy234 reveal a membrane-disruptive mechanism in bacterial ESKAPE pathogens
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Structural determinants of the scorpion venom peptide Uy234 reveal a membrane-disruptive mechanism in bacterial ESKAPE pathogens
Abstract
The growth-inhibiting effect of the peptide Uy234, present in the venom of the scorpion Urodacus yaschenkoi, has been investigated in two bacterial pathogens: Staphylococcus aureus ATCC 25923 and Acinetobacter baumannii AE12, the latter being a multidrug-resistant clinical isolate. In addition, its interaction with phospholipid bilayers has been studied using atomic force microscopy (AFM), permeability studies in GUVs, and molecular dynamics simulations. To this end, two inactivated variants of this peptide were analyzed: Uy234-C (non-amidated peptide) and Uy234-A (P9A mutant). Only the native peptide Uy234 exhibited bacteriostatic and bactericidal activity, whereas both variants lost this antimicrobial activity, highlighting the essential role of the C-terminal amidation and the proline residue at position 9. In both cases, there is evidence of the key effect that these two structural determinants have on the bioactivity of Uy234 against the two pathogens. In addition to quantifying in detail the minimum inhibitory and bactericidal concentrations for each microorganism, our study provides clear evidence of a membrane-damaging effect through bacterial cell viability assays with SYTO9/PI fluorophores. Notably, in SYTO9/PI assays performed with S. aureus, membrane damage was detected only in the presence of the native peptide Uy234, whereas no membrane disruption was observed for the P9A mutant or the non-amidated variant. Moreover, AFM imaging of supported POPE:POPG lipid bilayers revealed membrane thinning and lateral expansion upon interaction with Uy234 , while our studies with DOPC, POPC, and POPE:POPG GUVs indicate dose-dependent permeabilization effects for these model systems in response to interaction with this peptide. In contrast, the mutant peptide P9A is unable to permeabilize GUVs, which is consistent with the persistence of a higher degree of structural order for this mutant peptide, according to molecular dynamics simulations in the aqueous phase. These findings are consistent with a membrane-disruptive mechanism potentially involving peptide aggregation and transient pore formation for Uy234, making it an interesting therapeutic alternative against multidrug-resistant bacteria.
Villa-Merlan, A. K., Mescola, A., Alejandro, P., Fernandez-Sánchez, F., Alessandrini, A., Balleza, D., & Quintero-Hernández, V. Structural determinants of the scorpion venom peptide Uy234 reveal a membrane-disruptive mechanism in bacterial ESKAPE pathogens. Frontiers in Microbiology, 17, 1830314. https://doi.org/10.3389/fmicb.2026.1830314