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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 [...]

Interestingly, in strains MG1655 waaG and MG1655 waaC, which have a modified LPS but wild-type protein composition, we observe alterations in the polymyxin-induced crystalline structures compared to wild-type MG1655. If the lattice is indeed involving OMPs, their precise arrangement is mediated by the LPS molecules and wild-type LPS is required for the well-ordered hexagonal lattices. B replying to b G. Benn et al. I Nature Communications i https://doi.org/10.1038/s41467-023-40275-0 (2023) Benn et al. comment that the hexagonal lattices observed in outer membrane (OM) patches upon the addition of polymyxin might be formed by outer membrane proteins (OMPs). 1Outer membrane protein assemblies imaged by high-resolution atomic force microscopy (AFM).a-c AFM height images of OMVs collected from E. coli overexpressing OMPs. a Overview AFM height image of an OMV enriched in the OMP Tsx [8]. [Extracted from the article]

An Amendment to this paper has been published and can be accessed via a link at the top of the paper., 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 [...]

Fully synthetic medium-sized macrocyclic peptides mimicking the key β-hairpin and α-helical protein epitopes relevant in many protein–protein interactions have emerged as a novel class of drugs with the potential to fill an important gap between small molecules and proteins. Conformationally stabilized macrocyclic scaffolds represent ideal templates for medicinal chemists to incorporate bioactive peptide and protein pharmacophores in order to generate novel drugs to treat diseases with high unmet medical need. This review describes recent approaches to design and generate large libraries of such macrocycles, for hit identification, and for their efficient optimization. Finally, this review describes some of the most advanced protein epitope mimetic (PEM) macrocycles in clinical development. [ABSTRACT FROM AUTHOR]

The article provides information on the development of antimicrobial peptides targeting the lipopolysaccharide transport (Lpt) machinery as a potential solution to antimicrobial resistance. Through the use of thanatin-derived synthetic macrocyclic peptides, the researchers successfully developed antibiotics with potent activity against drug-resistant bacteria by disrupting the Lpt protein bridge, demonstrating their potential as effective treatments for antimicrobial-resistant infections.