Small Amphiphilic Peptides: Activity Against Broad Range of Drug-Resistant Bacteria and Structural Insight into Membranolytic Properties

Journal of Medicinal Chemistry. 2022. Vol. 65. No. 1. P. 665–687.

Lohan S., Mandal D., Choi W., Konshina A. G., Tiwari R., Efremov R., Maslennikov I. V., Parang K.

We report the synthesis and antibacterial activities of a series of amphiphilic membrane-active peptides composed, in part, of various non-genetically coded hydrophobic amino acids. Lead cyclic peptides, 8C and 9C, showed broad-spectrum activity against drug-resistant Gram-positive (MIC=1.5-6.2 µg/mL) and Gram-negative (MIC=12.5-25 µg/mL) bacteria. Cytotoxicity study showed the predominant lethal action of the peptides against bacteria as compared with mammalian cells. A plasma stability study revealed approximately 2-fold higher stability of lead cyclic peptides as compared to their linear counterparts after 24 h incubation. A calcein dye leakage experiment revealed the membranolytic effect of the cyclic peptides. Nuclear magnetic resonance spectroscopy and molecular dynamics simulations studies of the interaction of the peptides with phospholipid bilayer provided a solid structural basis explaining the membranolytic action of the peptides with atomistic details. These results highlight the potential of newly designed amphiphilic peptides as the next generation of peptide-based antibiotics.

Keywords: молекулярная динамика, Drug resistance, Bacteria, antimicrobial peptides, molecular dynamics, антимикробные пептиды, antibiotics, антибиотики, Бактерии, Cyclic Peptides, Peptide-Membrane Interactions, Membranolytic, циклические пептиды, устойчивость к лекарствам, взаимодействия пептид-мембрана, мембранолитический

Publication based on the results of: Supercomputer technologies, theory and atomistic multiscale modeling in materials physics and life sciences (2022)