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

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