Project

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Design and applications of protein epitope mimetics

Applicant Robinson John A.
Number 129724
Funding scheme Project funding
Research institution Organisch-chemisches Institut Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Organic Chemistry
Start/End 01.06.2010 - 31.05.2013
Approved amount 272'968.00
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All Disciplines (2)

Discipline
Organic Chemistry
Experimental Microbiology

Keywords (9)

peptide; antibiotic; peptidomimetic; Pseudomonas; bacteria; membrane-protein; gram negative bacteria; cell wall biosynthesis; pseudomonas aeruginosa

Lay Summary (English)

Lead
Lay summary
The main goal of this project is to investigate the mechanism of action of a new class of peptidomimetic antibiotics that are active against the important gram negative bacterium Pseudomonas aeruginosa.P. aeruginosa is an important human pathogen, especially in hospitals and in patients with cystic fibrosis, and is becoming increasingly difficult to treat due to the emergence of resistance to all commonly used classes of antibiotics. The discovery of new antibiotics, with a novel mode of action is scientifically of great interest, and could also be of great value in medicine, for the treatment of nosocomial infections caused by P. aeruginosa. This project should contribute towards an understanding of how the new class of peptidomimetic antibiotics function. This knowledge is important for the further clinical development of these antibiotics.Our recent studies show that these peptidomimetic antibiotics interact with the outer membrane protein LptD (also called Imp or OstA) in Pseudomonas aeruginosa, which is known to be important in the assembly of the outer lipopolysaccharide leaflet in the outer membrane. We have recently hypothesized that the mode of action of these antibiotics may involve inhibition of LptD function, which would disrupt outer membrane biosynthesis. An important goal of the work proposed here is to obtain evidence for this unique mode of action. In particular, we would continue with photoaffinity labeling experiments using peptidomimetic antibiotics containing photolabile probes in order to detect targets in the cell; we would perform experiments to show that the antibiotics inhibit the function of LptD; we would characterize the binding site for the antibiotics on LptD; we would study cell uptake of the antibiotics; we would study structure-activity relationships; and finally we would pursue efforts to discover new analogues with a broader spectrum of antimicrobial activity against other serious Gram negative bacterial human pathogens. Thus, strains of Acinetobacter baumanii, Burkholderia sp., Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa are now becoming increasingly resistant to some or all of the antibiotic classes commonly used to treat Gram-negative bacterial infections and prospects for finding new antibiotics for Gram-negative pathogens are especially poor. The results of this work, therefore, may have important implications in many areas of biological chemistry and medicine.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Max Bergmann lecture protein epitope mimetics in the age of structural vaccinology
Robinson J. A. (2013), Max Bergmann lecture protein epitope mimetics in the age of structural vaccinology, in J. Pept. Sci., 19(3), 127-140.
Inhibition of Lipopolysaccharide Transport to the Outer Membrane in Pseudomonas aeruginosa by Peptidomimetic Antibiotics.
Werneburg Martina, Zerbe Katja, Juhas Mario, Bigler Laurent, Stalder Urs, Kaech Andres, Ziegler Urs, Obrecht Daniel, Eberl Leo, Robinson John A (2012), Inhibition of Lipopolysaccharide Transport to the Outer Membrane in Pseudomonas aeruginosa by Peptidomimetic Antibiotics., in Chembiochem : a European journal of chemical biology, 13(12), 1767-75.
Protein epitope mimetics as anti-infectives
Robinson J. A. (2011), Protein epitope mimetics as anti-infectives, in Curr. Opin. Chem. Biol., 15(3), 379-386.
Structural Studies of ß-Hairpin Peptidomimetic Antibiotics that Target LptD in Pseudomonas sp.
Schmidt J., Patora-Komisarska K., Moehle K., Obrecht D., Robinson J. A., Structural Studies of ß-Hairpin Peptidomimetic Antibiotics that Target LptD in Pseudomonas sp., in Bioorganic and Medicinal Chemistry, 21.

Collaboration

Group / person Country
Types of collaboration
Polyphor AG Switzerland (Europe)
- Industry/business/other use-inspired collaboration
Mikrobiologie, UZH Switzerland (Europe)
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Max Bergmann Conference 01.10.2012 Velen, Germany
Zing Natural Products Symposium 10.02.2012 Tenerife, Spain
EUCHEM Conference on Stereochemistry 03.05.2011 Brunnen, Switzerland


Communication with the public

Communication Title Media Place Year
Media relations: print media, online media Bio builders International Innovation International 01.05.2012
Talks/events/exhibitions Scientifica 2012 German-speaking Switzerland 01.09.2012

Awards

Title Year
Max Bergmann Medal 2012

Associated projects

Number Title Start Funding scheme
146381 Synthetic Protein Epitope Mimetics and Applications as Anti-infectives 01.06.2013 Project funding
116176 Design and synthesis of peptidomimetics as antibacterials, antivirals and HIV-1 synthetic vaccine candidates 01.08.2007 Project funding
116176 Design and synthesis of peptidomimetics as antibacterials, antivirals and HIV-1 synthetic vaccine candidates 01.08.2007 Project funding

Abstract

The main goal of our research over several years has been to develop new approaches to synthetic peptidomimetics of biologically important epitopes in naturally occurring peptides and proteins. In this proposal, we plan to continue our earlier studies on peptidomimetics that are based on naturally occurring antimicrobial peptides and proteins. These peptidomimetics possess a unique spectrum of antimicrobial activity. Only one enantiomer possesses potent antimicrobial activity with MICs (Minimal Inhibitory Concentrations) in the low nanomolar range, only against Pseudomonas species, and with a non-lytic mechanism of action. Our recent studies show that these peptides interact with the outer membrane protein LptD (also called Imp or OstA) in Pseudomonas aeruginosa, which is known to act as a lipopolysaccharide (LPS) flippase in the last steps of outer membrane biogenesis. We have recently hypothesized that the mode of action of these antibiotics may involve inhibition of LptD flippase function, which would disrupt outer membrane biosynthesis. An important goal of the work proposed here is to obtain evidence for this unique mode of action. This would be the first example of an antimicrobial peptide functioning through an interaction with a key outer membrane protein in Gram-negative bacteria. P. aeruginosa is an important human pathogen, especially in hospitals and in patients with cystic fibrosis, and is becoming increasingly difficult to treat due to the emergence of resistance to all commonly used classes of antibiotics.In particular, we would continue with photoaffinity labeling experiments using peptidomimetic antibiotics containing photolabile probes in order to detect targets in the cell; we would perform experiments to show that the antibiotics inhibit the function of OstA/Imp/LptD; we would characterize the binding site for the antibiotics on LptD; we would study cell uptake of the antibiotics; we would study structure-activity relationships; and finally we would pursue efforts to discover new analogues with a broader spectrum of antimicrobial activity against other serious Gram negative bacterial human pathogens. Thus, strains of Acinetobacter baumanii, Burkholderia sp. Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa are now becoming increasingly resistant to some or all of the antibiotic classes commonly used to treat Gram-negative bacterial infections and prospects for finding new antibiotics for Gram-negative pathogens are especially poor. The results of this work, therefore, may have important implications in many areas of biological chemistry and medicine.
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