TY - JOUR

T1 - Optimization of the Central α-Amino Acid in Cystobactamids to the Broad-Spectrum, Resistance-Breaking Antibiotic CN-CC-861

AU - Kohnhäuser, Daniel

AU - Seedorf, Tim

AU - Cirnski, Katarina

AU - Heimann, Dominik

AU - Coetzee, Janetta

AU - Sordello, Sylvie

AU - Richter, Jana

AU - Stappert, Moritz

AU - Sabuco, Jean Francois

AU - Corbett, David

AU - Bacque, Eric

AU - Rox, Katharina

AU - Herrmann, Jennifer

AU - Vassort, Aurelie

AU - Muller, Rolf

AU - Kirschning, Andreas

AU - Bronstrup, Mark

N1 - Publisher Copyright: © 2024 The Authors. Published by American Chemical Society.

PY - 2024/10/10

Y1 - 2024/10/10

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85204890450&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.4c00927

DO - 10.1021/acs.jmedchem.4c00927

M3 - Article

C2 - 39303218

AN - SCOPUS:85204890450

VL - 67

SP - 17162

EP - 17190

JO - Journal of medicinal chemistry

JF - Journal of medicinal chemistry

SN - 0022-2623

IS - 19

ER -