☆ 4.5 Article

Hydroxy-tryptophan containing derivatives of tritrpticin: Modification of antimicrobial activity and membrane interactions

BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES (2015)

Journal

BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES

Volume 1848, Issue 1, Pages 277-288

Publisher

ELSEVIER

DOI: 10.1016/j.bbamem.2014.08.024

Keywords

Tritrpticin; 5-Hydroxy-tryptophan; Antimicrobial peptide; Membrane interaction; Membrane permeabilization

Funding

Canadian Institutes of Health Research
Natural Sciences and Engineering Research Council [293595-07]
Alberta Innovates-Health Solutions
Alberta Innovates [201200857] Funding Source: researchfish

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Abstract

Tritrpticin is an antimicrobial peptide with a strong microbicidal activity against Gram-positive and Gram-negative bacteria as well as fungi. The 13-residue peptide is essentially symmetrical and possesses a unique cluster of three Trp residues near the center of its amino acid sequence. The mechanism of action of tritrpticin is believed to involve permeabilization of the cytoplasmic membrane of susceptible bacteria. However it has been suggested that intracellular targets may also play a role in its antimicrobial activity. In this work the mechanism of action of several tritrpticin derivatives was studied through substitution of the three Trp residues with 5-hydroxytiyptophan (5OHW), a naturally occurring non-ribosomal amino acid. Although it is more polar, 5OHW preserves many of the biophysical and biochemical properties of Trp, allowing the use of fluorescence spectroscopy and NMR techniques to study the interaction of the modified peptides with membrane mimetics. Single or triple 5OHW substitution did not have a large effect on the MIC of the parent peptide against Escherichia coli and Bacillus subtilis. However, the mechanism of action was altered by simultaneously replacing all three Trp with 5OHW. Our results suggest that the inner membrane of Gram-negative bacteria did not constitute the main target of this particular tritrpticin derivative. Since the addition of a hydroxyl group to the indole motif of the Tip residue was able to modify the mechanism of action of the peptides, our data confirm the importance of the Trp cluster in tritrpticin. This work also shows that 5OHW constitutes a new probe to modulate the antimicrobial activity and mechanism of action of other Trp-rich antimicrobial peptides. This article is part of a Special Issue entitled: NMR Spectroscopy for Atomistic Views of Biomembranes and Cell Surfaces. Guest Editors: Lynette Cegelski and David P. Weliky. (C) 2014 Elsevier B.V. All rights reserved.

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Bactericidal Activity to Escherichia coli: Different Modes of Action of Two 24-Mer Peptides SAAP-148 and OP-145, Both Derived from Human Cathelicidine LL-37

Ayse Oen, Djenana Vejzovic, James Jennings, Lena Parigger, Robert A. Cordfunke, Jan Wouter Drijfhout, Karl Lohner, Nermina Malanovic

Summary: OP-145 and SAAP-148, derived from LL-37, show effective killing against both Gram-positive and Gram-negative bacteria. However, their impact on Escherichia coli does not align with membrane permeabilization. In this study, we used a combination of techniques to investigate their mode of action and found distinct binding patterns and permeabilization effects depending on the LPS phenotypes. Our findings suggest that depolarization of the cytoplasmic membrane and disruption of lipid packing are crucial for their bactericidal activity.

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