Abstract
A group of seven peptides from spider venom with diverse sequences constitute the latarcin family. They have been described as membrane-active antibiotics, but their lipid interactions have not yet been addressed. Using circular dichroism and solid-state 15N-NMR, we systematically characterized and compared the conformation and helix alignment of all seven peptides in their membrane-bound state. These structural results could be correlated with activity assays (antimicrobial, hemolysis, fluorescence vesicle leakage). Functional synergy was not observed amongst any of the latarcins. In the presence of lipids, all peptides fold into amphiphilic α-helices as expected, the helices being either surface-bound or tilted in the bilayer. The most tilted peptide, Ltc2a, possesses a novel kind of amphiphilic profile with a coiled-coil-like hydrophobic strip and is the most aggressive of all. It indiscriminately permeabilizes natural membranes (antimicrobial, hemolysis) as well as artificial lipid bilayers through the segregation of anionic lipids and possibly enhanced motional averaging. Ltc1, Ltc3a, Ltc4a, and Ltc5a are efficient and selective in killing bacteria but without causing significant bilayer disturbance. They act rather slowly or may even translocate towards intracellular targets, suggesting more subtle lipid interactions. Ltc6a and Ltc7, finally, do not show much antimicrobial action but can nonetheless perturb model bilayers.
Highlights
Our results show that the peptides with higher antimicrobial activity display higher hemolytic activity, suggesting that this effect is due to an intrinsic perturbation on the lipid bilayer
Our results clearly indicate that when peptides bind to the membrane, they may not fold completely, even though they seemed to fold from the circular dichroism spectroscopy (CD) line shapes in TFE or in the presence of bulk water; oriented CD (OCD) is a unique way of determining the fold change of the peptides in the membranous environment
We characterized the full set of latarcins in their membrane-bound state using CD, OCD, and NMR experiments
Summary
Depending on the organism’s habitat, many venoms are evolutionarily optimized to contain broad-spectrum antimicrobial peptides. Most of these short, amphiphilic, and often cationic AMPs tend to act on bacterial membranes and show an intrinsic tendency to destabilize the lipid bilayer. Amphiphilic, and often cationic AMPs tend to act on bacterial membranes and show an intrinsic tendency to destabilize the lipid bilayer This property of AMPs has been exploited since their discovery in the 1990s, with the aim of optimizing their potential against microbial infections, evaluating their cytotoxicity toward cancer cells, and reducing their hemolytic effects against erythrocytes, amongst other potential applications.
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