Chimeric peptidomimetic antibiotics against Gram-negative bacteria
| Autor: | Sarah Stiegeler, Caroline Kolopp, Alessandra Vitale, Maik Müller, Anatol Luther, Sophie Hell, Nicolas Desjonquères, Annie Vermeulen, Gregory Upert, Michel Schmitt, Petra Chiquet, Leo Eberl, Elizabeth Cline, Seyed Majed Modaresi, Virginie Rithié, Parthasarathi Rath, Fabio Lo Monte, Glenn E. Dale, Francesca Bernardini, Jean-Baptiste Hartmann, Marie-Anne Westwood, Achim Wach, Alexander Lederer, Régis Jaisson, Sebastian Hiller, Karen LePoupon, Daniel Obrecht, Hans H. Locher, Shuang-Yan Wang, John A. Robinson, Bernd Wollscheid, Milon Mondal, Carolin Verbree, Emile Brabet, Timothy Sharpe, Matthias Urfer, Gabriella Pessi, Peter Zbinden, Katja Zerbe, Harsha Kocherla, Tobias Remus, Michael Zahn, Kerstin Moehle |
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| Přispěvatelé: | University of Zurich, Obrecht, D |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Lipopolysaccharides
Male Models Molecular 0301 basic medicine Carbapenem Macrocyclic Compounds Gram-negative bacteria Peptidomimetic medicine.drug_class Polymyxin 030106 microbiology Antibiotics Microbial Sensitivity Tests Photoaffinity Labels 580 Plants (Botany) Fluorescence Microbiology Mice 03 medical and health sciences Microscopy Electron Transmission 10126 Department of Plant and Microbial Biology Drug Discovery Gram-Negative Bacteria medicine Animals Humans Biological Products 1000 Multidisciplinary Microbial Viability Multidisciplinary biology Chemistry Escherichia coli Proteins Drug Resistance Microbial biology.organism_classification Anti-Bacterial Agents 030104 developmental biology Mutation Colistin Peptidomimetics Bacterial outer membrane Bacteria Bacterial Outer Membrane Proteins medicine.drug |
| Popis: | There is an urgent need for new antibiotics against Gram-negative pathogens that are resistant to carbapenem and third-generation cephalosporins, against which antibiotics of last resort have lost most of their efficacy. Here we describe a class of synthetic antibiotics inspired by scaffolds derived from natural products. These chimeric antibiotics contain a β-hairpin peptide macrocycle linked to the macrocycle found in the polymyxin and colistin family of natural products. They are bactericidal and have a mechanism of action that involves binding to both lipopolysaccharide and the main component (BamA) of the β-barrel folding complex (BAM) that is required for the folding and insertion of β-barrel proteins into the outer membrane of Gram-negative bacteria. Extensively optimized derivatives show potent activity against multidrug-resistant pathogens, including all of the Gram-negative members of the ESKAPE pathogens1. These derivatives also show favourable drug properties and overcome colistin resistance, both in vitro and in vivo. The lead candidate is currently in preclinical toxicology studies that—if successful—will allow progress into clinical studies that have the potential to address life-threatening infections by the Gram-negative pathogens, and thus to resolve a considerable unmet medical need. A class of chimeric synthetic antibiotics that bind to lipopolysaccharide and BamA shows potent activity against multidrug-resistant Gram-negative bacteria, with the potential to address life-threatening infections. |
| Databáze: | OpenAIRE |
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