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Molecules (Basel, Switzerland)
Mar 30, 2021;26 (7):

Thrombin-Derived Peptides Potentiate the Activity of Gram-Positive-Specific Antibiotics against Gram-Negative Bacteria.

Charlotte M J Wesseling, Thomas M Wood, Kristine Bertheussen, Samantha Lok, Nathaniel I Martin
Author Information
  1. Charlotte M J Wesseling: Biological Chemistry Group, Institute of Biology Leiden, Leiden University, 2333 Leiden, The Netherlands. ORCID
  2. Thomas M Wood: Biological Chemistry Group, Institute of Biology Leiden, Leiden University, 2333 Leiden, The Netherlands.
  3. Kristine Bertheussen: Biological Chemistry Group, Institute of Biology Leiden, Leiden University, 2333 Leiden, The Netherlands. ORCID
  4. Samantha Lok: Biological Chemistry Group, Institute of Biology Leiden, Leiden University, 2333 Leiden, The Netherlands.
  5. Nathaniel I Martin: Biological Chemistry Group, Institute of Biology Leiden, Leiden University, 2333 Leiden, The Netherlands.
PMID: 33808488 DOI: 10.3390/molecules26071954

Abstract

The continued rise of antibiotic resistance threatens to undermine the utility of the world's current antibiotic arsenal. This problem is particularly troubling when it comes to Gram-negative pathogens for which there are inherently fewer antibiotics available. To address this challenge, recent attention has been focused on finding compounds capable of disrupting the Gram-negative outer membrane as a means of potentiating otherwise Gram-positive-specific antibiotics. In this regard, agents capable of binding to the lipopolysaccharide (LPS) present in the Gram-negative outer membrane are of particular interest as synergists. Recently, thrombin-derived C-terminal peptides (TCPs) were reported to exhibit unique LPS-binding properties. We here describe investigations establishing the capacity of TCPs to act as synergists with the antibiotics erythromycin, rifampicin, novobiocin, and vancomycin against multiple Gram-negative strains including polymyxin-resistant clinical isolates. We further assessed the structural features most important for the observed synergy and characterized the outer membrane permeabilizing activity of the most potent synergists. Our investigations highlight the potential for such peptides in expanding the therapeutic range of antibiotics typically only used to treat Gram-positive infections.

Keywords

LPS-targeting peptides antibiotic synergy checkerboard assays outer membrane disruption

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Grants

  1. 541001001/ZonMw
  2. 725523/European Research Council

MeSH Term

Anti-Infective Agents
Antimicrobial Cationic Peptides
Drug Resistance, Bacterial
Drug Synergism
Gram-Negative Bacteria
Thrombin

Chemicals

Anti-Infective Agents
Antimicrobial Cationic Peptides
Thrombin
Journal Article
Article has an altmetric score of 5

Word Cloud

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