Optimization of the Central α-Amino Acid in Cystobactamids to the Broad-Spectrum, Resistance-Breaking Antibiotic CN-CC-861

verfasst von

Daniel Kohnhäuser, Tim Seedorf, Katarina Cirnski, Dominik Heimann, Janetta Coetzee, Sylvie Sordello, Jana Richter, Moritz Stappert, Jean Francois Sabuco, David Corbett, Eric Bacque, Katharina Rox, Jennifer Herrmann, Aurelie Vassort, Rolf Muller, Andreas Kirschning, Mark Bronstrup

Abstract

Cystobactamids have a unique oligoarylamide structure and exhibit broad-spectrum activity against Gram-negative and Gram-positive bacteria. In this study, the central α-amino acid of the cystobactamid scaffold was modified to address the relevance of stereochemistry, hydrogen bonding and polarity by 33 derivatives. As demonstrated by three matched molecular pairs, l-amino acids were preferred over d-amino acids. A rigidification to a six-membered system stabilized the bioactive conformation for the on-target Escherichia coli gyrase, but did not improve antimicrobial activity. Compound CN-CC-861, carrying a propargyl side chain, had more than 16-fold lower minimal inhibitory concentration (MIC) values against Enterococcus faecalis, Staphylococci and Acinetobacter strains, compared to known analogues. Moreover, CN-CC-861 retained activity against multidrug-resistant enterococci, displayed strong bactericidal activity, moderate-low frequencies of resistance and in vivo efficacy in a neutropenic thigh infection model with E. coli. Overall, the findings will guide the design of new promising structures with higher activities and broader spectrum.

Organisationseinheit(en)

Institut für Organische Chemie
Zentrum für Biomolekulare Wirkstoffe (BMWZ)

Externe Organisation(en)

Helmholtz-Zentrum für Infektionsforschung GmbH (HZI)
Universität des Saarlandes
Evotec ID
Uppsala University

Typ

Artikel

Journal

Journal of medicinal chemistry

Band

67

Seiten

17162-17190

Anzahl der Seiten

29

ISSN

0022-2623

Publikationsdatum

10.10.2024

Publikationsstatus

Veröffentlicht

Peer-reviewed

Ja

ASJC Scopus Sachgebiete

Molekularmedizin, Wirkstoffforschung

Elektronische Version(en)

https://doi.org/10.1021/acs.jmedchem.4c00927 (Zugang: Offen)