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The Mechanism of Action of SAAP-148 Antimicrobial Peptide as Studied with NMR and Molecular Dynamics Simulations.

Authors :
Adélaïde M
Salnikov E
Ramos-Martín F
Aisenbrey C
Sarazin C
Bechinger B
D'Amelio N
Source :
Pharmaceutics [Pharmaceutics] 2023 Feb 24; Vol. 15 (3). Date of Electronic Publication: 2023 Feb 24.
Publication Year :
2023

Abstract

Background: SAAP-148 is an antimicrobial peptide derived from LL-37. It exhibits excellent activity against drug-resistant bacteria and biofilms while resisting degradation in physiological conditions. Despite its optimal pharmacological properties, its mechanism of action at the molecular level has not been explored.<br />Methods: The structural properties of SAAP-148 and its interaction with phospholipid membranes mimicking mammalian and bacterial cells were studied using liquid and solid-state NMR spectroscopy as well as molecular dynamics simulations.<br />Results: SAAP-148 is partially structured in solution and stabilizes its helical conformation when interacting with DPC micelles. The orientation of the helix within the micelles was defined by paramagnetic relaxation enhancements and found similar to that obtained using solid-state NMR, where the tilt and pitch angles were determined based on <superscript>15</superscript> N chemical shift in oriented models of bacterial membranes (POPE/POPG). Molecular dynamic simulations revealed that SAAP-148 approaches the bacterial membrane by forming salt bridges between lysine and arginine residues and lipid phosphate groups while interacting minimally with mammalian models containing POPC and cholesterol.<br />Conclusions: SAAP-148 stabilizes its helical fold onto bacterial-like membranes, placing its helix axis almost perpendicular to the surface normal, thus probably acting by a carpet-like mechanism on the bacterial membrane rather than forming well-defined pores.

Details

Language :
English
ISSN :
1999-4923
Volume :
15
Issue :
3
Database :
MEDLINE
Journal :
Pharmaceutics
Publication Type :
Academic Journal
Accession number :
36986623
Full Text :
https://doi.org/10.3390/pharmaceutics15030761