Progress in the Discovery of Treatments for C. difficile Infection: A Clinical and Medicinal Chemistry Review

Abstract

Clostridium difficile is an anaerobic, Gram-positive pathogen that causes C. difficile infection, which results in significant morbidity and mortality. The incidence of C. difficile infection in developed countries has become increasingly high due to the emergence of newer epidemic strains, a growing elderly population, extensive use of broad spectrum antibiotics, and limited therapies for this diarrheal disease. Because treatment options currently available for C. difficile infection have some drawbacks, including cost, promotion of resistance, and selectivity problems, new agents are urgently needed to address these challenges. This review article focuses on two parts: the first part summarizes current clinical treatment strategies and agents under clinical development for C. difficile infection; the second part reviews newly reported anti-difficile agents that have been evaluated or reevaluated in the last five years and are in the early stages of drug discovery and development. Antibiotics are divided into natural product inspired and synthetic small molecule compounds that may have the potential to be more efficacious than currently approved treatments. This includes potency, selectivity, reduced cytotoxicity, and novel modes of action to prevent resistance.

Resistance-resistant antibiotics

“…In addition, pentamidine can act as an uncoupler[69], as with SQ109. Moreover, DNA minor groove binders such as MGB-BP-3 (from MGB Biopharma) apparently function by targeting specific motifs in bacterial DNA, affecting transcription factor function but not cell growth[70, 71]. …”

Bis‐Cyclic Guanidines as a Novel Class of Compounds Potent against Clostridium difficile

“…However, to the best of our knowledge, compounds bearing guanidine groups [17] have been rarely explored for bactericidal activities against C. difficile . [18] Herein we report the antibacterial activity of these dimeric cyclic guanidines against C. difficile in vitro and in vivo.…”

Fecal microbiota transplantation in the treatment of refractory Clostridium difficile infection in children

“…The American Academy of Pediatrics recommends discontinuation of the antimicrobial as the first step in treating. For the treatment of RCDI, newer options have been proposed including rifaximin, nitazoxanide, fidaxomicin, tolevamer, probiotics, and immune-therapy; however, the safety and efficacy of these measures is yet to be studied in pediatric patients [3][4][5]. For the treatment of RCDI, newer options have been proposed including rifaximin, nitazoxanide, fidaxomicin, tolevamer, probiotics, and immune-therapy; however, the safety and efficacy of these measures is yet to be studied in pediatric patients [3][4][5].…”