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 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.