Nitro-Group-Containing Thiopeptide Derivatives as Promising Agents to Target Clostridioides difficile

Abstract

The US Centers for Disease Control and Prevention (CDC) lists Clostridioides difficile as an urgent bacterial threat. Yet, only two drugs, vancomycin and fidaxomicin, are approved by the FDA for the treatment of C. difficile infections as of this writing, while the global pipeline of new drugs is sparse at best. Thus, there is a clear and urgent need for new antibiotics against that organism. Herein, we disclose that AJ-024, a nitroimidazole derivative of a 26-membered thiopeptide, is a promising anti-C. difficile lead compound. Despite their unique mode of action, thiopeptides remain largely unexploited as anti-infective agents. AJ-024 combines potent in vitro activity against various strains of C. difficile with a noteworthy safety profile and desirable pharmacokinetic properties. Its time-kill kinetics against a hypervirulent C. difficile ribotype 027 and in vivo (mouse) efficacy compare favorably to vancomycin, and they define AJ-024 as a valuable platform for the development of new anti-C. difficile antibiotics.

Identification of Micrococcin P2-Derivatives as Antibiotic Candidates against Two Gram-Positive Pathogens

“…difficile. Moreover, 6d exhibits elevated antibacterial activity against Enterococcus species (MIC 50 : 0.25 μg/mL), including vancomycin-resistant Enterococcus . Clinical observations have shown that patients with colonized Enterococcus species in the large intestine tend to exhibit a poor clinical prognosis if they become infected with C.…”

“…The time-kill kinetics of 6d against ribotype 027 revealed a rapid onset of bactericidal action (Supporting Information). 39 Considering the low bioavailability of the compound, it is expected that its concentration in the large intestine would easily exceed the MIC value, resulting in rapid bactericidal action against C. difficile. Moreover, 6d exhibits elevated antibacterial activity against Enterococcus species (MIC 50 : 0.25 μg/mL), 39 including vancomycin-resistant Enterococcus.…”

“…39 Considering the low bioavailability of the compound, it is expected that its concentration in the large intestine would easily exceed the MIC value, resulting in rapid bactericidal action against C. difficile. Moreover, 6d exhibits elevated antibacterial activity against Enterococcus species (MIC 50 : 0.25 μg/mL), 39 including vancomycin-resistant Enterococcus. Clinical observations have shown that patients with colonized Enterococcus species in the large intestine tend to exhibit a poor clinical prognosis if they become infected with C. difficile.…”

“…Their elevated potency and other desirable properties qualify them as ideal starting points for the development of new antibiotics . The advent of robust synthetic methods for the production of decagram quantities of micrococcins has enabled a medicinal chemistry effort that led to the identification of preclinical candidates for impetigo (compound 6c ) and CDI (compound 6d ). , A detailed account of the medicinal chemistry and the optimization process for each indication are provided herein.…”

In vitro and intracellular activities of novel thiopeptide derivatives against macrolide-susceptible and macrolide-resistant Mycobacterium avium complex

“…Furthermore, AJ-024, a nitroimidazole derivative of a 26-membered thiopeptide based on MP2, was proven to be a promising anti -C . difficile lead compound ( 32 ). Thus, MP2 could be a valuable platform for the development of new antibiotics.…”