peptide; antibiotic; peptidomimetic; Pseudomonas; bacteria; membrane-protein; gram negative bacteria; cell wall biosynthesis; pseudomonas aeruginosa
Robinson J. A. (2013), Max Bergmann lecture protein epitope mimetics in the age of structural vaccinology, in J. Pept. Sci.
, 19(3), 127-140.
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.
Robinson J. A. (2011), Protein epitope mimetics as anti-infectives, in Curr. Opin. Chem. Biol.
, 15(3), 379-386.
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
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.