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

  • J Med Chem. 2024 Oct 10;67(19):17162-17190. doi: 10.1021/acs.jmedchem.4c00927.
Daniel Kohnhäuser  1 ,  Tim Seedorf  2 ,  Katarina Cirnski  3  4 ,  Dominik Heimann  1 ,  Janetta Coetzee  3  4 ,  Sylvie Sordello  5 ,  Jana Richter  1 ,  Moritz Stappert  1 ,  Jean-Francois Sabuco  5 ,  David Corbett  5 ,  Eric Bacqué  5 ,  Katharina Rox  1  4 ,  Jennifer Herrmann  3  4 ,  Aurelie Vassort  5 ,  Rolf Müller  3  4 ,  Andreas Kirschning  2  6 ,  Mark Brönstrup  1  2  4
Affiliations
  • 1. Department of Chemical Biology, Helmholtz Centre for Infection Research, Inhoffenstraße 7, 38124 Braunschweig, Germany.
  • 2. Institute of Organic Chemistry and Biomolecular Drug Research Centre (BMWZ), Leibniz University Hannover, Schneiderberg 1B, 30167 Hannover, Germany.
  • 3. Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Department of Pharmacy at Saarland University, Campus Building E8.1, 66123 Saarbrücken, Germany.
  • 4. German Center for Infection Research (DZIF), Site Hannover-Braunschweig, Inhoffenstraße 7, 38124 Braunschweig, Germany.
  • 5. Evotec ID, 1541 Avenue Marcel Merieux, 69289 Marcy l'Etoile, France.
  • 6. Uppsala Biomedical Center (BMC), Uppsala University, Husargatan 3, 752 37 Uppsala, Sweden.
PMID: 39303218 DOI: 10.1021/acs.jmedchem.4c00927
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.

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