Methods and Compositions for Inhibiting Clostridium difficile Spore Germination and Outgrowth

Abstract

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.

What is claimed is: 
     
         1 . (canceled) 
     
     
         2 . (canceled) 
     
     
         3 . A compound of Formula I 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is —CON(R 2 )CH 2 CH 2 (R 3 ); and 
 each of R 4  and R 5  is independently selected from the group consisting of —H, —OH, —O(R 2 ), and —OAcyl, 
 
         wherein:
 each R 2  is independently a straight or branched chain C1-C10 alkyl; and 
 R 3  is selected from the group consisting of —SO 3 (R 2 ) and —CO 2 (R 2 ); 
 
         wherein:
 when R 4  is either —H or —OH, R 5  is selected from the group consisting of —H, —O(R 2 ), and —OAcyl; and 
 when R 4  is either —O(R 2 ) or —OAcyl, R 5  is selected from the group consisting of —H, —OH, —O(R 2 ), and —OAcyl. 
 
       
     
     
         4 - 8 . (canceled) 
     
     
         9 . A method of preventing  Clostridium difficile -associated disease in a mammalian subject, comprising administering to a mammalian subject at risk of developing  C. difficile -associated disease an effective amount of a compound of Formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is selected from the group consisting of —CO 2 H, —CO 2 (R 2 ), —CONH 2 , —CON(R 2 ) 2 , —CONHCH 2 CH 2 (R 3 ), —CON(R 2 )CH 2 CH 2 (R 3 ), —NH 2 , —NH(R 2 ), and —N(R 2 ) 2 ; and 
 each of R 4  and R 5  is independently selected from the group consisting of —H, —NH 2 , —NH(R 2 ), —N(R 2 ) 2 , —OH, —O(R 2 ), and —OAcyl, 
 
         wherein:
 each R 2  is independently a straight or branched chain C1-C10 alkyl; and 
 R 3  is selected from the group consisting of —CO 2 H, —SO 3 H, —CONH 2 , —SO 2 NH 2 , —CO 2 (R 2 ), and —SO 3 (R 2 ), 
 
         to inhibit germination of  C. difficile  spores in the subject, thereby preventing  Clostridium difficile -associated disease in the subject. 
       
     
     
         10 - 21 . (canceled) 
     
     
         22 . The method of  claim 9 , wherein the  C. difficile -associated disease is  C. difficile  colitis. 
     
     
         23 . (canceled) 
     
     
         24 . The method of  claim 9 , wherein the subject at risk of developing the  C. difficile -associated disease is a subject that is receiving, is about to receive, or recently received an antibiotic associated with development of the  C. difficile -associated disease. 
     
     
         25 . The method of  claim 24 , wherein the antibiotic associated with the development of the  C. difficile -associated disease is selected from ampicillin, amoxicillin, clindamycin, fluoroquinolones, and cephalosporins. 
     
     
         26 . (canceled) 
     
     
         27 . The method of  claim 9 , wherein the administering is orally administering. 
     
     
         28 . (canceled) 
     
     
         29 . The method of any one of  claims 9 ,  22 ,  24 ,  25 , and  27 , wherein the subject is a human. 
     
     
         30 . 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:
 R 1  is selected from the group consisting of —CO 2 H, —CO 2 (R 2 ), —CONH 2 , —CON(R 2 ) 2 , —CONHCH 2 CH 2 (R 3 ), —CON(R 2 )CH 2 CH 2 (R 3 ), —NH 2 , —NH(R 2 ), and —N(R 2 ) 2 ; and 
 each of R 4  and R 5  is independently selected from the group consisting of —H, —NH 2 , —NH(R 2 ), —N(R 2 ) 2 , —OH, —O(R 2 ), and —OAcyl, 
 
         wherein:
 each R 2  is independently a straight or branched chain C1-C10 alkyl; and 
 R 3  is selected from the group consisting of —CO 2 H, —SO 3 H, —CONH 2 , —SO 2 NH 2 , —CO 2 (R 2 ), and —SO 3 (R 2 ), 
 
         to inhibit growth of  C. difficile  in the subject, thereby treating the  C. difficile -associated disease. 
       
     
     
         31 - 42 . (canceled) 
     
     
         43 . The method of  claim 30 , wherein the  C. difficile -associated disease is  C. difficile  colitis. 
     
     
         44 . (canceled) 
     
     
         45 . The method of  claim 30 , wherein the subject having the  C. difficile -associated disease is a subject that is receiving or recently received an antibiotic associated with development of the  C. difficile -associated disease. 
     
     
         46 . The method of  claim 45 , wherein the antibiotic associated with the development of the  C. difficile -associated disease is selected from ampicillin, amoxicillin, clindamycin, fluoroquinolones, and cephalosporins. 
     
     
         47 . (canceled) 
     
     
         48 . The method of  claim 30 , wherein the administering is orally administering. 
     
     
         49 . (canceled) 
     
     
         50 . The method of any one of  claims 30 ,  43 ,  45 ,  46 , and  48 , wherein the subject is a human. 
     
     
         51 - 89 . (canceled)