Compounds for the treatment of clostridium difficile infection
Inventors
Chang, Mayland • Mobashery, Shahriar • Ding, Derong
Assignees
Publication Number
US-12054466-B2
Publication Date
2024-08-06
Expiration Date
2037-09-12
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Abstract
Clostridium difficile infection (CDI) is a public health threat that results in 14,000 annual deaths in the United States. Challenges involve the production of CDI spores that can remain dormant for years and the production of toxins that damage the gut. Current therapies for CDI include vancomycin and metronidazole, but neither inhibits spore or toxin production. Thus, recurrence of infection occurs in 25% of patients and there are no antibiotics that are effective for multiple recurrences. We describe oxadiazoles with activity against C. difficile, including the highly virulent NAP1/027 strain with increased production of toxins A and B, as well as the additional binary toxin. Oxadiazole 2 is poorly absorbed, thus advantageously achieving high concentrations in the gut. The compound targets peptidoglycan synthesis and inhibits vegetative cells, spores, and toxin production.
Core Innovation
The invention relates to the discovery and use of novel oxadiazole compounds, particularly oxadiazole 2, for the treatment of Clostridium difficile infections (CDI). These compounds demonstrate potent activity not only against vegetative forms of C. difficile but also inhibit spore formation and toxin production, including inhibition of toxins A and B as well as the binary toxin in highly virulent strains.
A significant problem in the management of C. difficile infections is recurrence, as 25% of patients relapse after standard treatments and there are currently no antibiotics effective for multiple relapses. Existing antibiotics such as vancomycin and metronidazole do not inhibit spore or toxin production, leading to persistent infection and spread. Spores are resistant to cleaning agents and most antibiotics, and current therapies are ineffective against spore forms and toxin production.
The disclosed oxadiazole compounds provide a solution by being poorly absorbed when administered orally, enabling them to reach high concentrations in the gut, the site of C. difficile infection. These compounds specifically target peptidoglycan synthesis, effectively inhibiting vegetative cells, spore formation, and toxin production. The compounds were shown to be more effective than vancomycin in a mouse model of recurrent infection, demonstrating significant reductions in vegetative cell counts, spore counts, and toxin levels.
Claims Coverage
There are four independent inventive features covered in the claims, focusing on oxadiazole compound structures and their use for treating C. difficile infection.
Oxadiazole 2 compound
A compound represented by structure 2 is claimed. This includes its specific chemical structure as disclosed and described in the specification.
Treatment of C. difficile infection with oxadiazole 2
A method of treating a Clostridium difficile bacterial infection in the gastrointestinal tract of a subject by administering an effective amount of the compound according to structure 2.
Oxadiazole 3 compound
A compound represented by structure 3, as disclosed and described in the specification.
Treatment of C. difficile infection with oxadiazole viii or xxi
A method of treating a Clostridium difficile bacterial infection in a subject by administering an effective amount of a compound represented by structure viii or structure xxi.
The claims establish coverage for specific oxadiazole compounds and the therapeutic use of these compounds, particularly for treating Clostridium difficile infections in the gastrointestinal tract, including methods of oral administration.
Stated Advantages
The compounds are poorly absorbed, resulting in high concentrations in the gut where C. difficile infection occurs.
They inhibit C. difficile vegetative cells, as well as spore formation and toxin production, addressing limitations of existing antibiotics.
The oxadiazole compounds show better efficacy than vancomycin in a mouse model of recurrent C. difficile infection.
These compounds are well tolerated in mice and do not cause weight loss at therapeutically effective doses.
Documented Applications
Treatment of Clostridium difficile bacterial infection in the gastrointestinal tract of a subject, including humans.
Use in manufacturing medicaments useful for treatment of bacterial infections in a mammal, such as a human.
Medical therapy for infections by gram-positive spore-forming anaerobic bacteria.
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