Methods and compositions for inhibiting clostridium difficile spore germination and outgrowth
Certain bile acids, including novel bile acids, and derivatives thereof can be used to inhibit the germination of C. difficile spores and/or the growth of C. difficile cells. The methods and compositions of the invention are useful for preventing and treating C. difficile -associated diseases, including but not limited to C. difficile colitis.
1. A method of treating Clostridium difficile -associated disease in a mammalian subject, comprising administering to a mammalian subject having C. difficile -associated disease an effective amount of a compound of Formula I
or a pharmaceutically acceptable salt thereof, wherein:
the compound is an inhibitor of C. difficile spore germination;
R 1 is selected from the group consisting of —CO 2 H and −CO 2 (R 2 );
each R 2 is independently a straight or branched chain C1-C10 alkyl; and
each of R 4 and R 5 is independently selected from the group consisting of —OH and —OC(═O)(C1-C10 alkyl), to inhibit growth of C. difficile in the subject, thereby treating the C. difficile -associated disease, wherein the C. difficile -associated disease is selected from the group consisting of C. difficile colitis and pseudomembranous colitis.
2. The method of claim 1 , wherein the compound of Formula I is chenodeoxycholate or a pharmaceutically acceptable salt thereof.
3. The method of claim 1 , wherein the compound of Formula I is ursodeoxycholate or a pharmaceutically acceptable salt thereof.
4. The method of claim 1 , wherein the mammalian subject is a human.
5. The method of claim 1 , wherein:
R 1 is —CO 2 (R 2 );
R 2 is methyl; and
both R 4 and R 5 are —OH.
6. The method of claim 1 , wherein:
R 1 is —CO 2 (R 2 );
R 2 is methyl;
R 4 is —OH; and
R 5 is —OC(═O)(C1-C10 alkyl).
7. The method of claim 1 , wherein:
R 1 is —CO 2 (R 2 );
R 2 is methyl;
R 4 is —OH; and
R 5 is —OC(═O)(CH 3 ).
8. The method of claim 1 , wherein:
R 1 is —CO 2 (R 2 );
R 2 is methyl;
both R 4 and R 5 are —OC(═O)(C1-C10 alkyl).
9. The method of claim 1 , wherein:
R 1 is —CO 2 (R 2 );
R 2 is methyl;
both R 4 and R 5 are —OC(═O)(CH 3 ).
10. A method of reducing risk of developing Clostridium difficile -associated disease in a mammalian subject receiving antibiotic therapy, comprising administering to a mammalian subject receiving antibiotic therapy and at risk of developing C. difficile -associated disease an effective amount of a compound of Formula I
or a pharmaceutically acceptable salt thereof, wherein:
the compound is an inhibitor of C. difficile spore germination;
R 1 is selected from the group consisting of —CO 2 H and —CO 2 (R 2 );
each R 2 is independently a straight or branched chain C1-C10 alkyl; and
each of R 4 and R 5 is independently selected from the group consisting of —OH and —OC(═O)(C1-C10 alkyl), to inhibit germination of C. difficile spores in the subject, thereby reducing the risk of developing Clostridium difficile -associated disease in the subject, wherein the C. difficile -associated disease is selected from the group consisting of C. difficile colitis and pseudomembranous colitis.
11. The method of claim 10 , wherein:
R 1 is —CO 2 (R 2 );
R 2 is methyl; and
both R 4 and R 5 are —OH.
12. The method of claim 10 , wherein:
R 1 is —CO 2 (R 2 );
R 2 is methyl;
R 4 is —OH; and
R 5 is —OC(═O)(C1-C10 alkyl).
13. The method of claim 10 , wherein:
R 1 is —CO 2 (R 2 );
R 2 is methyl;
R 4 is —OH; and
R 5 is —OC(═O)(CH 3 ).
14. The method of claim 10 wherein:
R 1 is —CO 2 (R 2 );
R 2 is methyl;
both R 4 and R 5 are —OC(═O)(C1-C10 alkyl).
15. The method of claim 10 , wherein:
R 1 is —CO 2 (R 2 );
R 2 is methyl;
both R 4 and R 5 are —OC(═O)(CH 3 ).
16. The method of claim 10 , wherein the mammalian subject is a human.