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Luther, Anatol; Urfer, Matthias; Zahn, Michael; Müller, Maik; Wang, Shuang-Yan; Mondal, Milon; Vitale, Alessandra; Hartmann, Jean-Baptiste; Sharpe, Timothy; Monte, Fabio Lo; Kocherla, Harsha; Cline, Elizabeth; Pessi, Gabriella; Rath, Parthasarathi; Modaresi, Seyed Majed; Chiquet, Petra; Stiegeler, Sarah; Verbree, Carolin; Remus, Tobias; Schmitt, Michel; Kolopp, Caroline; Westwood, Marie-Anne; Desjonquères, Nicolas; Brabet, Emile; Hell, Sophie; LePoupon, Karen; Vermeulen, Annie; Jaisson, Régis; Rithié, Virginie; Upert, Grégory; Lederer, Alexander; Zbinden, Peter; Wach, Achim; Moehle, Kerstin; Zerbe, Katja; Locher, Hans H; Bernardini, Francesca; Dale, Glenn E; Eberl, Leo; Wollscheid, Bernd; Hiller, Sebastian; Robinson, John A; Obrecht, Daniel
Nature (London), 12/2019, Letnik: 576, Številka: 7787Journal Article
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 . 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.
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