pseudomonas aeryginosa; peptides; antimicrobials; biofilms; dendrimers
Siriwardena Thissa N., Capecchi Alice, Gan Bee-Ha, Jin Xian, He Runze, Wei Dengwen, Ma Lan, Köhler Thilo, van Delden Christian, Javor Sacha, Reymond Jean-Louis (2018), Optimizing Antimicrobial Peptide Dendrimers in Chemical Space, in Angewandte Chemie International Edition
, 57(28), 8483-8487.
Di Bonaventura Ivan, Baeriswyl Stéphane, Capecchi Alice, Gan Bee-Ha, Jin Xian, Siriwardena Thissa N., He Runze, Köhler Thilo, Pompilio Arianna, Di Bonaventura Giovanni, van Delden Christian, Javor Sacha, Reymond Jean-Louis (2018), An antimicrobial bicyclic peptide from chemical space against multidrug resistant Gram-negative bacteria, in Chemical Communications
, 54(40), 5130-5133.
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 (2017), Lipidated Peptide Dendrimers Killing Multidrug Resistant Bacteria, in JACS, Journal of the American Chemical Society
He Runze, Di Bonaventura Ivan, Visini Ricardo, Gan Bee Ha, Fu Yongchun, Probst Daniel, Lüscher Alexandre, Köhler Thilo, van Delden Christian, Stocker Achim, Hong Wenjing, Darbre Tamis, Reymond Jean-Louis (2017), Design, crystal structure and atomic force microscopy study of thioether ligated D,L-cyclic antimicrobial peptides against multidrug resistant Pseudomonas aeruginosa, in Chemical Science
, 2017(8), 7464-7475.
Di Bonaventura Ivan, Jin Xian, Visini Ricardo, Probst Daniel, Javor Sacha, Gan Bee Ha, Michaud Gaëlle, Natalello Antonio, Doglia Silvia Maria, Köhler Thilo, van Delden Christian, Stocker Achim, Darbre Tamis, Reymond Jean-Louis (2017), Chemical space guided discovery of antimicrobial bridged bicyclic peptides against Pseudomonas aeruginosa and its biofilms, in Chemical Science
, 2017(8), 6784-6798.
This proposal aims to explore the therapeutic potential and the microbiological mechanism of action of antimicrobial peptide with branched topologies recently discovered in the Reymond group. The Reymond group has recently established an efficient solid-phase peptide synthesis (SPPS) procedures to prepare peptides with branched (dendritic) and bicyclic topologies which are otherwise not accessible by natural biosynthetic pathways. These peptides offer a promising and versatile platform for drug design. This line of research is original and has not been followed by other groups in peptide chemistry, where research is focused almost exclusively on linear or monocyclic peptide analogs of natural sequences. In one of our line of research, we discovered that particular sequences of peptide dendrimers containing hydrophobic and cationic groups act as antimicrobial agents against various strains of Pseudomonas aeruginosa, a dangerous opportunistic pathogen. These new types of antimicrobials, called antimicrobial peptide dendrimers (AMPD), show much better resistance to proteolysis and lower hemolysis and cellular toxicity than linear antimicrobial peptides, suggesting that they might become useful antimicrobials in the clinic. In this project we will collaborate to understand the mechanism of action of AMPD through the identification of resistant mutants. We will also optimize the amino acid sequence of AMPD for higher activities against selected bacterial strains and test their efficacy in a mouse model of pulmonary infection. Our goal is to arrive at a clinical candidate antibiotic and the end of the 3 yrs project.