EcDBS1R6: A novel cationic antimicrobial peptide derived from a signal peptide sequence

• Published in: Biochimica et biophysica acta. General subjects Vol. 1864; no. 9; p. 129633
• Main Authors: Porto, William F., Irazazabal, Luz N., Humblot, Vincent, Haney, Evan F., Ribeiro, Suzana M., Hancock, Robert E.W., Ladram, Ali, Franco, Octavio L.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.09.2020; Elsevier
• Subjects: Amino Acid Sequence; Antimicrobial Cationic Peptides - chemistry; Antimicrobial Cationic Peptides - pharmacology; antimicrobial peptides; antimicrobial properties; bacteria; bacterial infections; Escherichia coli; Escherichia coli - chemistry; fluorescent dyes; Gram-Negative Bacteria - drug effects; image analysis; Joker algorithm; Life Sciences; Mechanism of action; Membrane damage; Microbial Sensitivity Tests; minimum inhibitory concentration; molecular dynamics; Molecular Dynamics Simulation; Protein Conformation; Protein Sorting Signals; Rational design; scanning electron microscopy; signal peptide; Sliding window; Rational design; Mechanism of action; Joker algorithm; Membrane damage; Sliding window
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2020.129633

Bacterial infections represent a major worldwide health problem the antimicrobial peptides (AMPs) have been considered as potential alternative agents for treating these infections. Here we demonstrated the antimicrobial activity of EcDBS1R6, a peptide derived from a signal peptide sequence of Escherichia coli that we previously turned into an AMP by making changes through the Joker algorithm. Antimicrobial activity was measured by broth microdilution method. Membrane integrity was measured using fluorescent probes and through scanning electron microscopy imaging. A sliding window of truncated peptides was used to determine the EcDBS1R6 active core. Molecular dynamics in TFE/water environment was used to assess the EcDBS1R6 structure. Signal peptides are known to naturally interact with membranes; however, the modifications introduced by Joker transformed this peptide into a membrane-active agent capable of killing bacteria. The C-terminus was unable to fold into an α-helix whereas its fragments showed poor or no antimicrobial activity, suggesting that the EcDBS1R6 antibacterial core was located at the helical N-terminus, corresponding to the signal peptide portion of the parent peptide. The strategy of transforming signal peptides into AMPs appears to be promising and could be used to produce novel antimicrobial agents. The process of transforming an inactive signal peptide into an antimicrobial peptide could open a new venue for creating new AMPs derived from signal peptides. [Display omitted] •EcDBS1R6 largely targets Gram-negative bacteria.•EcDBS1R6 has a safe in vitro selectivity index.•EcDBS1R6 acts on bacterial membranes.•The N-terminus contains the core of EcDBS1R6 activity.•EcDBS1R6 is an α-helical peptide with a dynamic C-terminus.