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Lipidated Peptide Dendrimers Killing Multidrug Resistant Bacteria

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Siriwardena Thissa N., Stach Michaela, He Runze, Gan Bee Ha, Javor Sacha, Heitz Marc, Ma Lan, Cai Xiangjun, Chen Peng, Wei Dengwen, Li Hongtao, Ma Jun, Koehler Thilo, van Delden Christian, Darbre Tamis, Reymond Jean-Louis,
Project Controlling multi-antibiotic resistant bacteria with antimicrobial peptide dendrimers (AMPD)
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Original article (peer-reviewed)

Journal JACS, Journal of the American Chemical Society
Page(s) 1 - 26
Title of proceedings JACS, Journal of the American Chemical Society
DOI 10.1021/jacs.7b11037

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 MRD bacteria worldwide. Our most active dendrimer TNS18 is also active against Gram-positive methicillin resistant Staphylococcus aureus (MRSA). 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 E. coli, suggesting that lipidated peptide dendrimers might become a new class of antibacterial agents.
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