Lipidated Peptide Dendrimers Killing Multidrug Resistant Bacteria
The paper Lipidated Peptide Dendrimers Killing Multidrug Resistant Bacteria has been accepted by the Journal of the American Chemical Society.
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.
Author(s): Thissa N. Siriwardena, Michaela Stach, Runze He, Bee-Ha Gan, Sacha Javor, Marc Heitz, Lan Ma, Xiangjun Cai, Peng Chen, Dengwen Wei, Hongtao Li, Jun Ma, Thilo Koehler, Christian van Delden, Tamis Darbre, and Jean-Louis Reymond