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Controlling multi-antibiotic resistant bacteria with antimicrobial peptide dendrimers (AMPD)

English title Controlling multi-antibiotic resistant bacteria with antimicrobial peptide dendrimers (AMPD)
Applicant Reymond Jean-Louis
Number 155982
Funding scheme Bilateral programmes
Research institution Departement für Chemie und Biochemie Universität Bern
Institution of higher education University of Berne - BE
Main discipline Organic Chemistry
Start/End 01.10.2015 - 30.09.2018
Approved amount 246'744.00
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All Disciplines (3)

Discipline
Organic Chemistry
Medical Microbiology
Infectious Diseases

Keywords (5)

pseudomonas aeryginosa; peptides; antimicrobials; biofilms; dendrimers

Lay Summary (French)

Lead
Peptides dendritiques antimicrobiens pour la lutte contre les souches bactériennes résistantes aux antibiotiques.
Lay summary
Dans ce projet nous allons explorer le potentiel thérapeutique de peptides antimicrobiens découverts récemment dans le groupe du Prof. Reymond. Ces peptides à forte activité antimicrobienne contres des souches multi-résistantes de la bactérie Pseudomonas aeruginosa, ont la particularité d’avoir une topologie multi-branchée de type « dendrimère » qui n’est pas observée dans la nature et peut seulement être réalisée par synthèse chimique par la méthode de synthèse en support solide. Cette topologie branchée leur confère des propriétés originales telles qu’une grande stabilité dans le sérum, et une toxicité cellulaire très basse. En collaboration avec le groupe du Prof. Qiao, nous allons tester l’activité de ces produits sur un plus large spectre de souches pathogènes et tenter de comprendre leur mécanisme d’action par l’étude de souches résistantes. Nous allons également tester l’activité des meilleurs peptides branchés dans un modèle animal d’infection pulmonaire. Notre but est d’identifier un produit pour le développement clinique dans un délai de trois ans. 
Direct link to Lay Summary Last update: 15.07.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Optimizing Antimicrobial Peptide Dendrimers in Chemical Space
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.
An antimicrobial bicyclic peptide from chemical space against multidrug resistant Gram-negative bacteria
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.
Lipidated Peptide Dendrimers Killing Multidrug Resistant Bacteria
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, 1-26.
Design, crystal structure and atomic force microscopy study of thioether ligated D,L-cyclic antimicrobial peptides against multidrug resistant Pseudomonas aeruginosa
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.
Chemical space guided discovery of antimicrobial bridged bicyclic peptides against Pseudomonas aeruginosa and its biofilms
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.

Collaboration

Group / person Country
Types of collaboration
College of Life Sciences, Nankai University, Prof. Mingqiang Qiao China (Asia)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Fall Meeting, Swiss Chemical Society Poster : Mechanism of Action of Antimicrobial Peptide Dendrimer G3KL revealed by Time Lapse Laser Scanning Confocal Microscope in Pseudomonas aeruginosa 07.09.2018 EPFL, Lausanne, Switzerland Gan Bee Ha;
SCS Fall Meeting 2018 Poster Crystallographic study of a Bicyclic peptide from Chemical Space 07.09.2018 EPFL, Lausanne, Switzerland Baeriswyl Stéphane;
IMAP Talk given at a conference Mechanism of Action of Antimicrobial Peptide Dendrimer G3KL revealed by Time Lapse Laser Scanning Confocal Microscope in Pseudomonas aeruginosa 02.09.2018 Edinburgh, Great Britain and Northern Ireland Gan Bee Ha;
Swiss Society of Microbiology Talk given at a conference Antimicrobial Peptide Dendrimers from Chemical Space and their Mechanism of Action 28.08.2018 CHUV, Lausanne, Switzerland Gan Bee Ha;
Summer School in Chemical Biology Poster Antimicrobial Peptide Dendrimers from Chemical Space and their Mechanism of Action 19.08.2018 Villars-sur-Ollon, Switzerland Gan Bee Ha;
Summer School in Chemical Biology Poster Crystallographic study of a Bicyclic peptide from Chemical Space 19.08.2018 Villars-sur-Ollon, Switzerland Baeriswyl Stéphane;
The 7th International Meeting on Antimicrobial Peptides (IMAP 2017) Poster Fluorescent Labeling of the Antimicrobial Peptide Dendrimer G3KL to Investigate its Mechanism of Action against Pseudomonas aeruginosa 25.08.2017 Copenhagen, Denmark Gan Bee Ha;
The 7th International Meeting on Antimicrobial Peptides (IMAP 2017) Talk given at a conference Chemical space guided discovery and optimization of topologically diverse antimicrobial peptides against Pseudomonas aeruginosa and its bioflms 25.08.2017 Copenhagen, Denmark Reymond Jean-Louis;
The 7th International Meeting on Antimicrobial Peptides (IMAP 2017) Talk given at a conference Microscopic Studies of Pseudomonas aeruginosa in the Presence of the Antimicrobial Peptide Dendrimer G3KL 25.08.2017 Copenhagen, Denmark Gan Bee Ha;
SCS Fall Meeting 2017 Poster Crystallography of antimicrobial peptide-Lectin complexes 21.08.2017 Bern, Switzerland Baeriswyl Stéphane;
SCS Fall Meeting 2017 Poster Fluorescent Labeling of the Antimicrobial Peptide Dendrimer G3KL to Investigate its Mechanism of Action against Pseudomonas aeruginosa 21.08.2017 Bern, Switzerland Gan Bee Ha;
Fall Meeting 2016 of Swiss Chemical Society Poster Fluorescent Labelling of the Antimicrobial Peptide Dendrimer G3KL to Investigate its Mechanism of Action against Pseudomonas aeruginosa 15.09.2016 Zürich, Switzerland Gan Bee Ha;
Summer School in Chemical Biology 2016 Poster Fluorescent Labelling of the Antimicrobial Peptide Dendrimer G3KL to Investigate its Mechanism of Action against Pseudomonas aeruginosa 21.08.2016 Villars-sur-Ollon, Switzerland Gan Bee Ha;
7th International Peptide Symposium 2015 Poster Antimicrobial Cyclic Peptides with L,D- architecture Targeting Pseudomonas aeruginosa 09.12.2015 Matrix Auditorium Level 2, Biopolis, Singapore, Singapore He Runze;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Open House at department of chemistry and biochemistry of the University of Bern German-speaking Switzerland 2016

Associated projects

Number Title Start Funding scheme
140349 Exploring Peptide Topologies in Search for New Drugs 01.04.2012 Project funding (Div. I-III)
167048 Antimicrobial peptide dendrimers (AMPD) and bicyclic peptides (AMBP) as therapeutic agents against multidrug resistant bacteria 01.03.2017 NRP 72 Antimicrobial Resistance
164025 Automated Peptide Purification System 01.01.2016 R'EQUIP
178998 Chemical Space Design of Small Molecules and Peptides 01.04.2018 Project funding (Div. I-III)
173709 GlycoSTART: Structure and function of eukaryotic oligosaccharyltransferase 01.06.2017 Sinergia

Abstract

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.
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