Inhibitors of C. difficile spore germination
Inventors
Abel-Santos, Ernesto • Firestine, Steven • Sharma, Shiv • Schilke, Angel • Yip, Christopher • Phan, Jacqueline
Assignees
Boards Of Governors Of Wayne State University • Boards Of Regents Of Nevada System Of Higher Education On Behalf Of University Of Nevada Las Vegas • Boards Of Regents Of Nevada System Of Higher Education On Behalf Of University Of Nevada Las • Wayne State University
Publication Number
US-12220421-B2
Publication Date
2025-02-11
Expiration Date
2042-09-09
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Abstract
Provided herein are compounds, compositions, and methods useful for reducing, preventing, and/or inhibiting germination of C. difficile spores, including methods for inhibiting C. difficile germination to prevent or treating C. difficile-associated diseases and disorders such as, for example, severe diarrhea and colitis in a subject. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
Core Innovation
The invention relates to compounds, compositions, and methods that are useful for reducing, preventing, or inhibiting the germination of Clostridium difficile spores. These compounds have defined chemical structures, often based on analogs of bile acids, and can be formulated into compositions suitable for administration to subjects. The methods encompass both therapeutic and preventive approaches, including administration for inhibiting C. difficile spore germination to prevent or treat C. difficile-associated diseases and disorders such as severe diarrhea and colitis.
The problem addressed is the significant clinical and economic burden of C. difficile infections, which are predominantly transmitted via hardy, germination-resistant spores. Existing natural and synthetic bile acids or analogs have shown either limited effectiveness or lack activity against hypervirulent C. difficile strains, and some are not sufficiently potent or are metabolically unstable. Therefore, there remains a need for novel compounds and compositions that efficiently inhibit spore germination and prevent development or recurrence of C. difficile infections.
The invention discloses novel compounds with specific heteroaryl and bicyclic structures, including benzoxazole, benzimidazole, benzothiazole, quinazolinone, and tertiary amide derivatives, many of which show potent in vitro anti-germination activity against C. difficile spores, including hypervirulent strains (e.g., R20291). These compounds can be incorporated into feed compositions or pharmaceutical formulations and administered to human or animal subjects to prevent or treat diseases associated with C. difficile infection, targeting the spore germination step to disrupt pathogenesis.
Claims Coverage
The patent contains independent claims directed to compounds, compositions containing these compounds, and methods of use for preventing or treating C. difficile infections or inhibiting spore germination.
Novel compounds inhibiting C. difficile spore germination
The invention claims compounds having a specific structure wherein each of R1, R2a, and R2b is independently selected from hydrogen and —OH, and Ar1 is a bicyclic heteroaryl (as defined) with tailored substituents including various heteroatoms and alkyl, alkoxy, halogen, and phenyl groups, or a pharmaceutically acceptable salt thereof. - The claimed structures include detailed options for the Ar1 group, including various heterocyclic ring systems and substituents. - The compounds may be present in stereoisomeric forms, tautomers, or as prodrugs or salts as described in the specification.
Compositions comprising an effective amount of the compound and a feed component
A composition is claimed which comprises an effective amount of the aforementioned compound and a feed component such as a vegetable protein, fat-soluble vitamin, water-soluble vitamin, trace mineral, macro mineral, or their combination. Such compositions can be formulated as granules or pellets.
Method for preventing or treating C. difficile infection in a subject
A method is claimed for preventing or treating a disease or disorder caused by infection of Clostridium difficile in a subject, comprising administering to the subject an effective amount of one of the claimed compounds or a pharmaceutically acceptable salt thereof. - The method may further comprise administering an antibiotic. - The method can be used when the disease or disorder is severe diarrhea or colitis. - The method may also include administering a composition comprising the compound and a feed component.
In summary, the claims cover specifically defined anti-germination compounds, compositions incorporating these compounds into feed or other pharmaceutical forms, and methods of using these to prevent or treat C. difficile infection or related disorders.
Stated Advantages
The compounds inhibit germination of C. difficile spores and thereby prevent diseases caused by infection of C. difficile, such as severe diarrhea and colitis.
Use of these anti-germinants reduces the possibility of resistance development because replicating bacteria are not under selective pressure.
The compounds can be optimized for retention in the gastrointestinal tract, avoiding systemic absorption and maximizing effectiveness in the gut.
In animal models, selected compounds provide complete protection from C. difficile infection, including hypervirulent strains, and demonstrate stability against degradation by the microbiota.
Documented Applications
Inhibiting germination of C. difficile spores in humans or animals to prevent or treat C. difficile-associated diseases, such as severe diarrhea and colitis.
Use in feed compositions for domesticated or farmed animals (including poultry and livestock) to reduce or prevent C. difficile-related adverse effects.
Therapeutic administration to human subjects for preventing or treating diseases caused by C. difficile infection.
Co-administration with antibiotics or as part of combination therapy regimens against C. difficile infections.
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