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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 [beta]-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 [beta]-barrel folding complex (BAM) that is required for the folding and insertion of [beta]-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.sup.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. A class of chimeric synthetic antibiotics that bind to lipopolysaccharide and BamA shows potent activity against multidrug-resistant Gram-negative bacteria, with the potential to address life-threatening infections., Author(s): Anatol Luther [sup.1] , Matthias Urfer [sup.2] , Michael Zahn [sup.3] , Maik Müller [sup.4] , Shuang-Yan Wang [sup.2] , Milon Mondal [sup.2] , Alessandra Vitale [sup.5] , Jean-Baptiste [...]

This review describes a selection of macrocyclic natural products and structurally modified analogs containing peptidic and non-peptidic elements as structural features that potentially modulate cellular permeability. Examples range from exclusively peptidic structures like cyclosporin A or phepropeptins to compounds with mostly non-peptidic character, such as telomestatin or largazole. Furthermore, semisynthetic approaches and synthesis platforms to generate general and focused libraries of compounds at the interface of cyclic peptides and non-peptidic macrocycles are discussed.