ABSTRACT
An Amendment to this paper has been published and can be accessed via a link at the top of the paper.
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 ß-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 ß-barrel folding complex (BAM) that is required for the folding and insertion of ß-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.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Drug Resistance, Microbial , Gram-Negative Bacteria/drug effects , Peptidomimetics/chemistry , Peptidomimetics/pharmacology , Animals , Anti-Bacterial Agents/adverse effects , Bacterial Outer Membrane Proteins/chemistry , Bacterial Outer Membrane Proteins/genetics , Biological Products/chemistry , Drug Discovery , Drug Resistance, Microbial/drug effects , Escherichia coli Proteins/chemistry , Escherichia coli Proteins/genetics , Fluorescence , Gram-Negative Bacteria/genetics , Gram-Negative Bacteria/pathogenicity , Humans , Lipopolysaccharides/chemistry , Macrocyclic Compounds/adverse effects , Macrocyclic Compounds/chemistry , Macrocyclic Compounds/pharmacology , Male , Mice , Microbial Sensitivity Tests , Microbial Viability/drug effects , Microscopy, Electron, Transmission , Models, Molecular , Mutation , Peptidomimetics/adverse effects , Photoaffinity LabelsABSTRACT
The glycogen synthase kinase 3 (GSK-3) is implicated in multiple cellular processes and has been linked to the pathogenesis of Alzheimer's disease (AD). In the course of our research topic we synthesized a library of potent GSK-3 inhibitors. We utilized the urea scaffold present in the potent and highly selective GSK-3 inhibitor AR-A014418 (AstraZeneca). This moiety suits both (a) a convergent approach utilizing readily accessible building blocks and (b) a divergent approach based on a microwave heating assisted Suzuki coupling. We established a chromatography-free purification method to generate products with sufficient purity for the biological assays. The structure-activity relationship of the library provided the rationale for the synthesis of the benzothiazolylurea 66 (IC(50)=140 nM) and the pyridylurea 62 (IC(50)=98 nM), which displayed two to threefold enhanced activity versus the reference compound 18 (AR-A014418: IC(50)=330 nM) in our assays.
