文献类型：期刊文献

英文题名：Lipidated Peptide Dendrimers Killing Multidrug-Resistant Bacteria

作者：Siriwardena, Thissa N.[1];Stach, Michaela[1];He, Runze[1,2];Gan, Bee-Ha[1];Javor, Sacha[1];Heitz, Marc[1];Ma, Lan[2,3,4];Cai, Xiangju[3];Chen, Peng[5];Wei, Dengwen[5];Li, Hongtao[5];Ma, Jun[3];Kohler, Thilo[6];van Delden, Christian[6,7];Darbre, Tamis[1];Reymond, Jean-Louis[1]

第一作者：Siriwardena, Thissa N.

通信作者：Darbre, T[1];Reymond, JL[1]

机构：[1]Univ Bern, Dept Chem & Biochem, Freiestr 3, CH-3012 Bern, Switzerland;[2]Shanghai Space Peptides Pharmaceut Co Ltd, Shanghai 201210, Peoples R China;[3]Gansu Univ Chinese Med, Coll Pharm, Dingxi East Rd 35, Lanzhou 730000, Gansu, Peoples R China;[4]Lanzhou Ruibei Pharmaceut R&D Co Ltd, Lanzhou 730000, Gansu, Peoples R China;[5]PLA, Lanzhou Gen Hosp Lanzhou Mil Reg, Dept Gen Surg, 333 South Binhe Rd, Lanzhou 730046, Gansu, Peoples R China;[6]Univ Geneva, Dept Microbiol & Mol Med, CH-1211 Geneva, Switzerland;[7]Univ Hosp Geneva, Serv Infect Dis, CH-1205 Geneva, Switzerland

第一机构：Univ Bern, Dept Chem & Biochem, Freiestr 3, CH-3012 Bern, Switzerland

通信机构：[1]corresponding author), Univ Bern, Dept Chem & Biochem, Freiestr 3, CH-3012 Bern, Switzerland.

年份：2018

卷号：140

期号：1

起止页码：423

外文期刊名：JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

收录：;EI(收录号：20180304646377);Scopus(收录号：2-s2.0-85040339215);WOS:【SCI-EXPANDED(收录号:WOS:000422813300074)】；

基金：This work was supported financially by the Swiss National Science Foundation (grant nos. 200020159941, IZLCZ2155982, and NRP72) and the Swiss TransMed (B5 platform project).

语种：英文

外文关键词：Chains - Dichroism - Escherichia coli - Cell death - Fatty acids - Molecular dynamics - Peptides

摘要：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.