Work

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

Year: 2024

Type: article

Abstract: High Resolution Image Download MS PowerPoint Slide 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.

Source: Journal of Medicinal Chemistry

DOI: 10.1021/acs.jmedchem.4c00927