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 SchmittCaroline 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, Daniel Obrecht

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Article number0
Pages (from-to)452-458
Number of pages7
Early online date23 Oct 2019
Publication statusPublished - 19 Dec 2019


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