Discovery and Structure–Activity Relationship of Cadazolid: A First-In-Class Quinoxolidinone Antibiotic for the Treatment of Clostridioides difficile Infection

Clostridioides difficile (C. difficile) is one of the leading
causes of healthcare-associated
infections worldwide. The increasing incidence of strains resistant
to currently available therapies highlights the need for alternative
treatment options with a novel mode of action. Oxazolidinones that
are connected to a quinolone moiety with a pyrrolidine linker, such
as compound 1, are reported to exhibit potent broadspectrum
antibacterial activity. In an effort to optimize this class of compounds
for the treatment of C. difficile infection
(CDI), we have identified cadazolid (9), a first-in-class
quinoxolidinone antibiotic, which is a potent inhibitor of C. difficile protein synthesis. In order to achieve
narrow-spectrum coverage of clinically most relevant strains without
affecting the gut microbiota, an emphasis was placed on abolishing
activity against commensals of the intestinal microbiome while retaining
good coverage of pathogenic C. difficile, including hypervirulent and epidemic strains.