Optimization\nof the Central α‑Amino Acid\nin Cystobactamids to the Broad-Spectrum, Resistance-Breaking Antibiotic\nCN-CC-861

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