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    Linearized esculentin-2EM shows pH dependent antibacterial activity with an alkaline optimum

    Year: 2021

    Journal: Mol. Cell. Biochem., Volume 476, OCT, page 3729–3744

    Authors: Malik, Erum; Phoenix, David A.; Snape, Timothy J.; Harris, Frederick; Singh, Jaipaul; Morton, Leslie H. G.; Dennison, Sarah R.

    Organizations: Shah Abdul Latif University, Pakistan via the Higher Education Commission, Pakistan

    Keywords: Linearized esculentin 2EM (E2EM-lin); alpha-Helical structure; pH dependent with alkaline optimum; Tilted peptide; Preference for gram-positive bacteria

    Here the hypothesis that linearized esculentin 2EM (E2EM-lin) from Glandirana emeljanovi possesses pH dependent activity is investigated. The peptide showed weak activity against Gram-negative bacteria (MLCs >= 75.0 mu M) but potent efficacy towards Gram-positive bacteria (MLCs <= 6.25 mu M). E2EM-lin adopted an a-helical structure in the presence of bacterial membranes that increased as pH was increased from 6 to 8 (up arrow 15.5-26.9%), whilst similar increases in pH enhanced the ability of the peptide to penetrate (up arrow 2.3-5.1 mN m(-1)) and lyre (up arrow 15.1-32.5%) these membranes. Theoretical analysis predicted that this membranolytic mechanism involved a tilted segment, that increased along the a-helical long axis of E2EM-lin (1-23) in the N -> C direction, with - increasing overall from circa - 0.8 to - 0.3. In combination, these data showed that E2EM-lin killed bacteria via novel mechanisms that were enhanced by alkaline conditions and involved the formation of tilted and membranolytic, a-helical structure. The preference of E2EM-lin for Gram-positive bacteria over Gram-negative organisms was primarily driven by the superior ability of phosphatidylglycerol to induce a-helical structure in the peptide as compared to phosphatidylethanolamine. These data were used to generate a novel pore-forming model for the membranolytic activity of E2EM-lin, which would appear to be the first, major reported instance of pH dependent AMPs with alkaline optima using tilted structure to drive a pore-forming process. It is proposed that E2EM-lin has the potential for development to serve purposes ranging from therapeutic usage, such as chronic wound disinfection, to food preservation by killing food spoilage organisms.
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