Chimeric peptidomimetic antibiotics against Gram-negative bacteria.

Autor: Luther A; Polyphor AG, Allschwil, Switzerland., Urfer M; Chemistry Department, University of Zurich, Zurich, Switzerland., Zahn M; Biozentrum, University of Basel, Basel, Switzerland., Müller M; Institute of Molecular Systems Biology & Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland., Wang SY; Chemistry Department, University of Zurich, Zurich, Switzerland., Mondal M; Chemistry Department, University of Zurich, Zurich, Switzerland., Vitale A; Department of Plant and Microbial Biology, University of Zurich, Zurich, Switzerland., Hartmann JB; Biozentrum, University of Basel, Basel, Switzerland., Sharpe T; Biozentrum, University of Basel, Basel, Switzerland., Monte FL; Chemistry Department, University of Zurich, Zurich, Switzerland., Kocherla H; Chemistry Department, University of Zurich, Zurich, Switzerland., Cline E; Chemistry Department, University of Zurich, Zurich, Switzerland., Pessi G; Department of Plant and Microbial Biology, University of Zurich, Zurich, Switzerland., Rath P; Biozentrum, University of Basel, Basel, Switzerland., Modaresi SM; Biozentrum, University of Basel, Basel, Switzerland., Chiquet P; Polyphor AG, Allschwil, Switzerland., Stiegeler S; Polyphor AG, Allschwil, Switzerland., Verbree C; Polyphor AG, Allschwil, Switzerland., Remus T; Polyphor AG, Allschwil, Switzerland., Schmitt M; Polyphor AG, Allschwil, Switzerland., Kolopp C; Polyphor AG, Allschwil, Switzerland., Westwood MA; Polyphor AG, Allschwil, Switzerland., Desjonquères N; Polyphor AG, Allschwil, Switzerland., Brabet E; Polyphor AG, Allschwil, Switzerland., Hell S; Polyphor AG, Allschwil, Switzerland., LePoupon K; Polyphor AG, Allschwil, Switzerland., Vermeulen A; Polyphor AG, Allschwil, Switzerland., Jaisson R; Polyphor AG, Allschwil, Switzerland., Rithié V; Polyphor AG, Allschwil, Switzerland., Upert G; Polyphor AG, Allschwil, Switzerland., Lederer A; Polyphor AG, Allschwil, Switzerland., Zbinden P; Polyphor AG, Allschwil, Switzerland., Wach A; Polyphor AG, Allschwil, Switzerland., Moehle K; Chemistry Department, University of Zurich, Zurich, Switzerland., Zerbe K; Chemistry Department, University of Zurich, Zurich, Switzerland., Locher HH; Polyphor AG, Allschwil, Switzerland., Bernardini F; Polyphor AG, Allschwil, Switzerland., Dale GE; Polyphor AG, Allschwil, Switzerland., Eberl L; Department of Plant and Microbial Biology, University of Zurich, Zurich, Switzerland., Wollscheid B; Institute of Molecular Systems Biology & Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland., Hiller S; Biozentrum, University of Basel, Basel, Switzerland., Robinson JA; Chemistry Department, University of Zurich, Zurich, Switzerland. john.robinson@chem.uzh.ch., Obrecht D; Polyphor AG, Allschwil, Switzerland. daniel.obrecht@polyphor.com.
Jazyk: angličtina
Zdroj: Nature [Nature] 2019 Dec; Vol. 576 (7787), pp. 452-458. Date of Electronic Publication: 2019 Oct 23.
DOI: 10.1038/s41586-019-1665-6
Abstrakt: 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.
Databáze: MEDLINE
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