Optimization of the Central α-Amino Acid in Cystobactamids to the Broad-Spectrum, Resistance-Breaking Antibiotic CN-CC-861
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 <i>Escherichia coli</i> 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 <i>Enterococcus faecalis</i>, <i>Staphylococci</i> and <i>Acinetobacter</i> 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 <i>in vivo</i> efficacy in a neutropenic thigh infection model with <i>E. coli</i>. Overall, the findings will guide the design of new promising structures with higher activities and broader spectrum.
Authors
- Dominik Heimann (ORCID: https://orcid.org/0000-0001-7821-4672)
- Jana K. Richter (ORCID: https://orcid.org/0000-0002-9294-3430)
- Aurélie Vassort
- Daniel Kohnhäuser
- Katarina Cirnski
- Mark Brönstrup (ORCID: https://orcid.org/0000-0002-8971-7045)
- Katharina Rox (ORCID: https://orcid.org/0000-0002-8020-1384)
- Janetta Coetzee (ORCID: https://orcid.org/0000-0002-6961-8445)
- Sylvie Sordello
- Eric Bacqué (ORCID: https://orcid.org/0000-0002-9339-5050)
- Andreas Kirschning (ORCID: https://orcid.org/0000-0001-5431-6930)
- Jean-François Sabuco
- Rolf Müller (ORCID: https://orcid.org/0000-0002-1042-5665)
- Tim Seedorf
- Jennifer E. Herrmann (ORCID: https://orcid.org/0000-0003-3398-9938)
- David F. Corbett
- Moritz Stappert
Institutions
- Leibniz University Hannover (DE)
- Uppsala University (SE)
- German Center for Infection Research (DE)
- Helmholtz Centre for Infection Research (DE)
- Helmholtz Institute for Pharmaceutical Research Saarland (DE)
- Saarland University (DE)
- Evotec (United States) (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-09-20
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c00927
- Citations
- 5
- Primary Topic
- Antibiotic Resistance in Bacteria
- Type
- article
- Field-Weighted Citation Impact
- 0.85
Funders
- Deutsches Zentrum für Infektionsforschung
- Bundesministerium für Bildung und Forschung
- Gottfried Wilhelm Leibniz Universität Hannover
- Universität des Saarlandes
- Uppsala Universitet
- Leibniz-Gemeinschaft