Reducing risk of contracting clostridium-difficile associated disease

Abstract

A method of treating a patient to reduce risk of developing Clostridium difficile-associated disease or reducing existing Clostridium difficile-associated disease in a mammalian subject involves administering to a mammalian subject an effective amount of a germination-inhibiting compound derived from taurocholate. Novel compounds of this class are also provided.

What is claimed: 
     
       1. A method of treating Clostridium difficile-associated disease in a subject that has been diagnosed with Clostridium difficile-associated disease prior to treatment, the method comprising administering to a mammalian subject a therapeutically effective amount of a compound having a structure represented by a formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       2. The method of  claim 1 , wherein the subject is concurrently receiving antibiotic therapy. 
     
     
       3. The method of  claim 1 , wherein the subject is human. 
     
     
       4. The method of  claim 1 , wherein the subject is a farm animal. 
     
     
       5. A method for inhibiting germination of a Clostridium difficile spore in a subject, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein each of R 1  and R 2  is independently selected from hydrogen, halogen, —OH, —NH 2 , —CN, —CO 2 H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, and C1-C6 hydroxyalkyl, 
         wherein R 3  is selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl; 
         wherein R 4  is selected from O and S; and 
         wherein R 5  is —NH(CH 2 ) 4 CO 2 H, —NH(CH 2 ) 4 CONH(CH 2 ) 4 COOH, —NH(CH 2 ) 5 CO 2 H, —NH(CH 2 ) 5 CONH(CH 2 ) 5 COOH, —S(CH 2 ) 2 SO 3 H, —NHCH 2 PO 3 H, —NHC 6 H 5 , —NHC 5 H 4 N, —NH(p-C 6 H 4 )CO 2 H, —NH(o-C 6 H 4 )CO 2 H, —NH(m-C 6 H 4 )CO 2 H, —NH(m-C 6 H 4 )CO 2 CH 3 , —NH(m-C 6 H 4 )OPO 3 H 2 , —NH(o-C 6 H 4 )OH, —NH(m-C 6 H 4 )OH, —NH(o-C 6 H 4 )SH, —NH(m-C 6 H 4 )SH, —NH(m-C 6 H 4 )SCH 3 , —NH(m-C 6 H 4 )NH 2 , —NH(m-C 6 H 4 )CH 3 , —NH(o-CH 3 -m-(C 6 H 3 ))SO 3 H, —NH(o-OCH 3 -m-(C 6 H 3 ))SO 3 H, —NH(o-CH 3 -m-(C 6 H 3 ))CO 2 H, —NH(p-CH 3 -m-(C 6 H 3 ))CO 2 H, —NH(o,p-(CH 3 ) 2 -m-(C 6 H 2 ))SO 3 H, —NH(p,m-(CH 3 ) 2 -m-(C 6 H 2 ))SO 3 H, and —NCH 3 (m-C 6 H 4 )SO 3 H, 
         or a pharmaceutically acceptable salt thereof, 
         thereby inhibiting germination of the Clostridium difficile spore in the subject.  
       
     
     
       6. The method of claim 5, wherein each of R 1  and R 2  is —OH.  
     
     
       7. The method of claim 5, wherein R 3  is hydrogen.  
     
     
       8. The method of claim 5, wherein R 4 is oxygen.  
     
     
       9. The method of claim 5, wherein R 5  is —NH(CH 2 ) 4 CO 2 H, —NH(CH 2 ) 5 CO 2 H, —NHC 6 H 5 , —NH(p-C 6 H 4 )CO 2 H, —NH(m-C 6 H 4 )NH 2 , —NH(p-CH 3 -m-(C 6 H 3 ))CO 2 H, —NH(o,p-(CH 3 ) 2 -m-(C 6 H 2 ))SO 3 H, —NH(p,m-(CH 2 ) 2 -m-(C 6 H 2 ))SO 3 H, —NH(CH 2 ) 4 CONH(CH 2 ) 4 COOH, —NH(CH 2 ) 5 CONH(CH 2 ) 5 COOH, and —NH(m-C 6 H 4 )CO 2 H.  
     
     
       10. The method of claim 5, wherein the subject is a human or a farm animal.  
     
     
       11. The method of claim 5, further comprising administering to the subject an antibiotic.  
     
     
       12. The method of claim 11, wherein the antibiotic is selected from metronidazole, amoxicillin, levofloxacin, clarithromycin, vancomycin, fusidic acid, rifamycin, teicoplanin, and bacitracin.  
     
     
       13. The method of claim 5, wherein the effective amount is a prophylactically effective amount.  
     
     
       14. The method of claim 5, wherein the subject is not concurrently receiving antibiotic therapy.  
     
     
       15. A method for inhibiting germination of a Clostridium difficile spore in a subject, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein R 4  is selected from O and S; and 
         wherein R 5  is selected from —NHCH 2 SO 3 H, —NH(CH 2 ) 2 SO 3 H, —NH(CH 2 ) 2 SO 3 H, —NH(p-C 6 H 4 )SO 3 H, —NH(o-C 6 H 4 )SO 3 H, —NH(m-C 6 H 4 )SO 3 H, —NHCH 2 CO 2 H, —NH(CH 2 ) 2 CO 2 H, —NH(CH 2 ) 2 CONH(CH 2 ) 2 CO 2 H, —NH(CH 2 ) 4 CO 2 H, —NH(CH 2 ) 4 CONH(CH 2 ) 4 COOH, —NH(CH 2 ) 5 CO 2 H, —NH(CH 2 ) 5 CONH(CH 2 ) 5 COOH, —S(CH 2 ) 2 SO 3 H, —NHCH 2 PO 3 H, —NHC 6 H 5 , —NHC 5 H 4 N, —NH(p-C 6 H 4 )CO 2 H, —NH(o-C 6 H 4 )CO 2 H, —NH(m-C 6 H 4 )CO 2 H, —NH(m-C 6 H 4 )CO 2 CH 3 , —NH(m-C 6 H 4 )OPO 3 H 2 , —NH(o-C 6 H 4 )OH, —NH(m-C 6 H 4 )OH, —NH(o-C 6 H 4 )SH, —NH(m-C 6 H 4 )SH, —NH(m-C 6 H 4 )SCH 3 , —NH(m-C 6 H 4 )NH 2 , —NH(m-C 6 H 4 )CH 3 , —NH(o-CH 3 -m-(C 6 H 3 ))SO 3 H, —NH(o-OCH 3 -m-(C 6 H 3 ))SO 3 H, —NH(o-CH 3 -m-(C 6 H 3 ))CO 2 H, —NH(p-CH 3 -m-(C 6 H 3 ))CO 2 H, —NH(o,p-(CH 3 ) 2 -m-(C 6 H 2 ))SO 3 H, —NH(p,m-(CH 3 ) 2 -m-(C 6 H 2 ))SO 3 H, and —NCH 3 (m-C 6 H 4 )SO 3 H, 
         or a pharmaceutically acceptable salt thereof, 
         provided that the compound is not: 
       
       
         
           
           
               
               
           
         
         thereby inhibiting germination of the Clostridium difficile spore in the subject.  
       
     
     
       16. The method of claim 15, wherein R 4  is oxygen.  
     
     
       17. The method of claim 15, wherein R 5  is —NH(CH 2 ) 4 CO 2 H, —NH(CH 2 ) 5 CO 2 H, —NHC 6 H 5 , —NH(p-C 6 H 4 )CO 2 H, —NH(m-C 6 H 4 )NH 2 , —NH(p-CH 3 -m-(C 6 H 3 ))CO 2 H, —NH(o,p-(CH 3 ) 2 -m-(C 6 H 2 ))SO 3 H, —NH(p,m-(CH 3 ) 2 -m-(C 6 H 2 ))SO 3 H, —NH(CH 2 ) 4 CONH(CH 2 ) 4 COOH, —NH(CH 2 ) 5 CONH(CH 2 ) 5 COOH, or —NH(m-C 6 H 4 )CO 2 H.