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Chimeric peptidomimetic antibiotics against Gram-negative bacteria

Luther, Anatol and Urfer, Matthias and Zahn, Michael and Müller, Maik and Wang, Shuang-Yan and Mondal, Milon and Vitale, Alessandra and Hartmann, Jean-Baptiste and Sharpe, Timothy and Monte, Fabio Lo and Kocherla, Harsha and Cline, Elizabeth and Pessi, Gabriella and Rath, Parthasarathi and Modaresi, Seyed Majed and Chiquet, Petra and Stiegeler, Sarah and Verbree, Carolin and Remus, Tobias and Schmitt, Michel and Kolopp, Caroline and Westwood, Marie-Anne and Desjonquères, Nicolas and Brabet, Emile and Hell, Sophie and LePoupon, Karen and Vermeulen, Annie and Jaisson, Régis and Rithié, Virginie and Upert, Grégory and Lederer, Alexander and Zbinden, Peter and Wach, Achim and Moehle, Kerstin and Zerbe, Katja and Locher, Hans H. and Bernardini, Francesca and Dale, Glenn E. and Eberl, Leo and Wollscheid, Bernd and Hiller, Sebastian and Robinson, John A. and Obrecht, Daniel. (2019) Chimeric peptidomimetic antibiotics against Gram-negative bacteria. Nature, 576 (7787). pp. 452-458.

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Official URL: https://edoc.unibas.ch/74986/

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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 pathogens; 1; . 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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Hiller)
05 Faculty of Science > Departement Biozentrum > Services Biozentrum > Biophysics Facility (Sharpe)
UniBasel Contributors:Hiller Odermatt, Sebastian and Sharpe, Timothy
Item Type:Article, refereed
Article Subtype:Research Article
ISSN:1476-4687
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:25 Mar 2020 04:10
Deposited On:10 Feb 2020 16:45

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