Conformational Flexibility and Net Charge are Key Determinants for the Antimicrobial Activity of Peptide Uy234 Against Multidrug-resistant Bacteria

Abstract

Background The antimicrobial activity of two peptides, Uy234 derived from the venom of the scorpion Urodacus yaschenkoi and a consensus peptide QnCs-Buap, was evaluated. We tested different pathogenic bacteria: Acinetobacter baumannii, Klebsiella pneumoniae, Salmonella enterica, Bacillus subtilis, Enterococcus spp. and Staphylococcus aureus , including one methicillin resistant (MRSA) and two multidrug resistant (MDR) clinical isolates. In contrast to the QnCs-Buap peptide, Uy234 showed relevant growth inhibitory activity on A. baumannii and B. subtilis , and mostly on S. aureus strains. Objective The present research focused on elucidating the mechanism for this antibacterial activity. Methodology We carried out an in-depth analysis of the composition, structure, flexibility, and physicochemical properties of both peptides. Results We found a crucial role of the C-terminal amide and composition in favoring the formation of a dense H-bond network in the Uy234 peptide. This H-bonding network slightly stiffens the peptide and keeps it in a preordered conformation in the aqueous phase. Conclusions We hypothesize that, given that Uy234 is a very short peptide (18 aa), it could have a destabilizing effect and favor micellization phenomena instead forming pores. In contrast, the QnCs-Buap peptide (13 aa), having only the positive charge at the N-terminal end and being significantly more hydrophobic and rigid, is not capable of overcoming the energy barrier to disturb the membrane. We propose that Uy234 peptide can be a scaffold to develop new derivatives with high potential against infections caused by diverse multidrug-resistant bacteria. Graphical Abstract

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