Lipidated Peptide Dendrimers Killing Multidrug-Resistant Bacteria.

Autor:	Siriwardena TN; Department of Chemistry and Biochemistry, University of Bern , Freiestrasse 3, 3012 Bern, Switzerland., Stach M; Department of Chemistry and Biochemistry, University of Bern , Freiestrasse 3, 3012 Bern, Switzerland., He R; Department of Chemistry and Biochemistry, University of Bern , Freiestrasse 3, 3012 Bern, Switzerland.; Shanghai Space Peptides Pharmaceutical Co. Ltd , Shanghai 201210, China., Gan BH; Department of Chemistry and Biochemistry, University of Bern , Freiestrasse 3, 3012 Bern, Switzerland., Javor S; Department of Chemistry and Biochemistry, University of Bern , Freiestrasse 3, 3012 Bern, Switzerland., Heitz M; Department of Chemistry and Biochemistry, University of Bern , Freiestrasse 3, 3012 Bern, Switzerland., Ma L; Shanghai Space Peptides Pharmaceutical Co. Ltd , Shanghai 201210, China.; College of Pharmacy, Gansu University of Chinese Medicine , Dingxi East Road 35, Chenguan District, Lanzhou, Gansu Province 730000, China.; Lanzhou Ruibei Pharmaceutical R&D Co., Ltd. , Lanzhou, Gansu Province 730000, China., Cai X; College of Pharmacy, Gansu University of Chinese Medicine , Dingxi East Road 35, Chenguan District, Lanzhou, Gansu Province 730000, China., Chen P; Department of General Surgery, Lanzhou General Hospital of Lanzhou Military Region , PLA, 333 South Binhe Road, Qilihe District, Lanzhou, Gansu Province 730046, China., Wei D; Department of General Surgery, Lanzhou General Hospital of Lanzhou Military Region , PLA, 333 South Binhe Road, Qilihe District, Lanzhou, Gansu Province 730046, China., Li H; Department of General Surgery, Lanzhou General Hospital of Lanzhou Military Region , PLA, 333 South Binhe Road, Qilihe District, Lanzhou, Gansu Province 730046, China., Ma J; College of Pharmacy, Gansu University of Chinese Medicine , Dingxi East Road 35, Chenguan District, Lanzhou, Gansu Province 730000, China., Köhler T; Department of Microbiology and Molecular Medicine, University of Geneva , CH-1211 Geneva, Switzerland., van Delden C; Department of Microbiology and Molecular Medicine, University of Geneva , CH-1211 Geneva, Switzerland.; Service of Infectious Diseases, University Hospital of Geneva , CH-1205 Geneva, Switzerland., Darbre T; Department of Chemistry and Biochemistry, University of Bern , Freiestrasse 3, 3012 Bern, Switzerland., Reymond JL; Department of Chemistry and Biochemistry, University of Bern , Freiestrasse 3, 3012 Bern, Switzerland.
Jazyk:	angličtina
Zdroj:	Journal of the American Chemical Society [J Am Chem Soc] 2018 Jan 10; Vol. 140 (1), pp. 423-432. Date of Electronic Publication: 2017 Dec 19.
DOI:	10.1021/jacs.7b11037
Abstrakt:	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.
Databáze:	MEDLINE
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