Chimeric peptidomimetic antibiotics against Gram-negative bacteria

Anatol Luther, Matthias Urfer, Michael Zahn, Maik Müller, Shuang-Yan Wang, Milon Mondal, Alessandra Vitale, Jean-Baptiste Hartmann, Timothy Sharpe, Fabio Lo Monte, Harsha Kocherla, Elizabeth Cline, Gabriella Pessi, Parthasarathi Rath, Seyed Majed Modaresi, Petra Chiquet, Sarah Stiegeler, Carolin Verbree, Tobias Remus, Michel Schmitt, Caroline Kolopp, Marie-Anne Westwood, Nicolas Desjonquères, Emile Brabet, Sophie Hell, Karen LePoupon, Annie Vermeulen, Régis Jaisson, Virginie Rithié, Grégory Upert, Alexander Lederer, Peter Zbinden, Achim Wach, Kerstin Moehle, Katja Zerbe, Hans H. Locher, Francesca Bernardini, Glenn E. Dale, Leo Eberl, Bernd Wollscheid, Sebastian Hiller, John A. Robinson () and Daniel Obrecht ()
Additional contact information
Anatol Luther: Polyphor AG
Matthias Urfer: University of Zurich
Michael Zahn: University of Basel
Maik Müller: ETH Zurich
Shuang-Yan Wang: University of Zurich
Milon Mondal: University of Zurich
Alessandra Vitale: University of Zurich
Jean-Baptiste Hartmann: University of Basel
Timothy Sharpe: University of Basel
Fabio Lo Monte: University of Zurich
Harsha Kocherla: University of Zurich
Elizabeth Cline: University of Zurich
Gabriella Pessi: University of Zurich
Parthasarathi Rath: University of Basel
Seyed Majed Modaresi: University of Basel
Petra Chiquet: Polyphor AG
Sarah Stiegeler: Polyphor AG
Carolin Verbree: Polyphor AG
Tobias Remus: Polyphor AG
Michel Schmitt: Polyphor AG
Caroline Kolopp: Polyphor AG
Marie-Anne Westwood: Polyphor AG
Nicolas Desjonquères: Polyphor AG
Emile Brabet: Polyphor AG
Sophie Hell: Polyphor AG
Karen LePoupon: Polyphor AG
Annie Vermeulen: Polyphor AG
Régis Jaisson: Polyphor AG
Virginie Rithié: Polyphor AG
Grégory Upert: Polyphor AG
Alexander Lederer: Polyphor AG
Peter Zbinden: Polyphor AG
Achim Wach: Polyphor AG
Kerstin Moehle: University of Zurich
Katja Zerbe: University of Zurich
Hans H. Locher: Polyphor AG
Francesca Bernardini: Polyphor AG
Glenn E. Dale: Polyphor AG
Leo Eberl: University of Zurich
Bernd Wollscheid: ETH Zurich
Sebastian Hiller: University of Basel
John A. Robinson: University of Zurich
Daniel Obrecht: Polyphor AG

Nature, 2019, vol. 576, issue 7787, 452-458

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41586-019-1665-6

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