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Scientific article
English

Lipidated peptide dendrimers killing multidrug-resistant bacteria

Published inJournal of the American Chemical Society, vol. 140, no. 1, p. 423-432
Publication date2018
Abstract

New antibiotics are urgently needed to address multidrug-resistant (MDR) bacteria. Herein we report that second-generation (G2) peptide dendrimers bearing a fatty acid chain at the dendrimer core efficiently kill Gram-negative bacteria including Pseudomonas aeruginosa and Acinetobacter baumannii, two of the most problematic MDR bacteria worldwide. Our most active dendrimer TNS18 is also active against Gram-positive methicillin-resistant Staphylococcus aureus. Based on circular dichroism and molecular dynamics studies, we hypothesize that TNS18 adopts a hydrophobically collapsed conformation in water with the fatty acid chain backfolded onto the peptide dendrimer branches and that the dendrimer unfolds in contact with the membrane to expose its lipid chain and hydrophobic residues, thereby facilitating membrane disruption leading to rapid bacterial cell death. Dendrimer TNS18 shows promising in vivo activity against MDR clinical isolates of A. baumannii and Escherichia coli, suggesting that lipidated peptide dendrimers might become a new class of antibacterial agents.

Keywords
  • Acinetobacter baumannii/drug effects
  • Animals
  • Anti-Bacterial Agents/chemistry/pharmacology
  • Dendrimers/chemistry/pharmacology
  • Dose-Response Relationship
  • Drug
  • Drug Resistance
  • Bacterial/drug effects
  • Escherichia coli/drug effects
  • Lipids/chemistry/pharmacology
  • Mice
  • Microbial Sensitivity Tests
  • Molecular Conformation
  • Peptides/chemistry/pharmacology
  • Pseudomonas aeruginosa/drug effects
  • Structure-Activity Relationship
Citation (ISO format)
SIRIWARDENA, Thissa N et al. Lipidated peptide dendrimers killing multidrug-resistant bacteria. In: Journal of the American Chemical Society, 2018, vol. 140, n° 1, p. 423–432. doi: 10.1021/jacs.7b11037
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ISSN of the journal0002-7863
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