Biophysical studies on the antimicrobial activity of linearized esculentin 2EM

Malik, Erum, Phoenix, David A, Badiani, Kamal, Snape, Timothy J, Harris, Frederick, Singh, Jaipaul orcid iconORCID: 0000-0002-3200-3949, Morton, Leslie Hugh Glyn and Dennison, Sarah Rachel orcid iconORCID: 0000-0003-4863-9607 (2020) Biophysical studies on the antimicrobial activity of linearized esculentin 2EM. Biochimica et biophysica acta. Biomembranes, 1862 (2). p. 183141. ISSN 0005-2736

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Linearized esculentin 2 EM (E2EM-lin) from the frog, Glandirana emeljanovi was highly active against Gram-positive bacteria (minimum lethal concentration ≤ 5.0 μM) and strongly α-helical in the presence of lipid mimics of their membranes (>55.0%). The N-terminal α-helical structure adopted by E2EM-lin showed the potential to form a membrane interactive, tilted peptide with an hydrophobicity gradient over residues 9 to 23. E2EM-lin inserted strongly into lipid mimics of membranes from Gram-positive bacteria (maximal surface pressure changes ≥5.5 mN m ), inducing increased rigidity (C ↑), thermodynamic instability (ΔG  < 0 → ΔG  > 0) and high levels of lysis (>50.0%). These effects appeared to be driven by the high anionic lipid content of membranes from Gram-positive bacteria; namely phosphatidylglycerol (PG) and cardiolipin (CL) species. The high levels of α-helicity (60.0%), interaction (maximal surface pressure change = 6.7 mN m ) and lysis (66.0%) shown by E2EM-lin with PG species was a major driver in the ability of the peptide to lyse and kill Gram-positive bacteria. E2EM-lin also showed high levels of α-helicity (62.0%) with CL species but only low levels of interaction (maximal surface pressure change = 2.9 mN m ) and lysis (21.0%) with the lipid. These combined data suggest that E2EM-lin has a specificity for killing Gram-positive bacteria that involves the formation of tilted structure and appears to be primarily driven by PG-mediated membranolysis. These structure/function relationships are used to help explain the pore forming process proposed to describe the membranolytic, antibacterial action of E2EM-lin. [Abstract copyright: Crown Copyright © 2019. Published by Elsevier B.V. All rights reserved.]

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