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Lipidated peptide dendrimers killing multidrug-resistant bacteria

Siriwardena, Thissa N
Stach, Michaela
He, Runze
Gan, Bee-Ha
Javor, Sacha
Heitz, Marc
Ma, Lan
Cai, Xiangju
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Published in Journal of the American Chemical Society. 2018, vol. 140, no. 1, p. 423-432
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 effectsAnimalsAnti-Bacterial Agents/chemistry/pharmacologyDendrimers/chemistry/pharmacologyDose-Response RelationshipDrugDrug ResistanceBacterial/drug effectsEscherichia coli/drug effectsLipids/chemistry/pharmacologyMiceMicrobial Sensitivity TestsMolecular ConformationPeptides/chemistry/pharmacologyPseudomonas aeruginosa/drug effectsStructure-Activity Relationship
PMID: 29206041
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Research group Quorom-sensing et gènes de virulence (301)
Swiss National Science Foundation: 200020_159941
Swiss National Science Foundation: IZLCZ2_155982
Swiss National Science Foundation: 200020159941; IZLCZ2155982; NRP72
(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 https://archive-ouverte.unige.ch/unige:144222

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Deposited on : 2020-11-05

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