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

Abstract

Clostridioides difficile (C. difficile) is one of the leading causes of healthcareassociated 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.

Current and Ongoing Developments in Targeting Clostridioides difficile Infection and Recurrence

“…A recent study revealed that cadazolid has potent and selective antibacterial activity against clinically important strains of C. difficile and acts by targeting the bacterial protein synthesis machinery. Cadazolid is essentially insoluble in the gastrointestinal tract, a major prerequisite for achieving high drug concentrations at the site of infection as well as minimizing potential side effects due to systemic Cadazolid has now advanced to Phase III clinical trials [144].…”

“…Cadazolid is essentially insoluble in the gastrointestinal tract, a ma jor prerequisite for achieving high drug concentrations at the site of infection as well as minimizing potential side effects due to systemic uptake. Cadazolid has now advanced to Phase III clinical trials [144]. A small library of eleven 4-substituted 2-aminoimidazoles was screened for efficacy against C. difficile, with compounds 17 (MIC50 = 2.5-5 mg/mL), 18 (MIC50 = 5 mg/mL), and 19 (MIC50 = 5 mg/mL) (Figure 8) having the most potent in vitro activities.…”

“…Cadazolid is essentially insoluble in the gastrointestinal tract, a major prerequisite for achieving high drug concentrations at the site of infection as well as minimizing potential side effects due to systemic uptake. Cadazolid has now advanced to Phase III clinical trials [ 144 ].…”