Inhibiting Germination of Clostridium Perfringens Spores to Reduce Necrotic Enteritis

Abstract

Provided herein are materials and methods useful for reducing, preventing, and/or inhibiting germination of C. perfringens spores, including methods for inhibiting C. perfringens germination to reduce necrotizing enteritis (NE, also referred to as necrotic enteritis) in animals. 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.

1 . A method for preventing a disease caused by infection by  Clostridium perfringens  in a subject, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein Q is selected from O, S, and NR 3 ;
 wherein R 3 , when present, is selected from hydrogen and C1-C8 alkyl; 
 
         wherein Z is selected from O, S, and NR 4 ;
 wherein R 4 , when present, is selected from hydrogen and C1-C8 alkyl; 
 
         wherein R 1  is selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, —CR 5a R 5b (C═O)NHN═CR 6 Ar 1 , Cy 1 , and Ar 2 , provided that if Q is NR 3  then R 1  is not —CR 5a R 5b (C═O)R 5 ;
 wherein each of R 5a  and R 5b , when present, is independently selected from hydrogen and C1-C4 alkyl; 
 wherein R 6 , when present, is selected from hydrogen and C1-C4 alkyl; 
 wherein Cy 1  is selected from C3-C7 cycloalkyl and C2-C7 heterocycloalkyl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; 
 wherein Ar 1  is selected from aryl and heteroaryl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; 
 wherein Ar 2  is selected from aryl and heteroaryl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and 
 
         wherein each of R 2a , R 2b , R 2c , and R 2d  is independently selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, 
         thereby preventing the disease caused by infection by  Clostridium perfringens  in a subject. 
       
     
     
         2 . The method of  claim 1 , wherein R 1  is selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, Cy 1 , and Ar 2 . 
     
     
         3 . The method of  claim 1 , wherein R 1  is C1-C4 alkyl. 
     
     
         4 . The method of  claim 1 , wherein each of R 2a , R 2b , R 2c , and R 2d  is hydrogen. 
     
     
         5 . The method of  claim 1 , wherein Z is selected from O and NR 4 ;
 wherein R 1  is selected from hydrogen, C1-C3 alkyl, and C1-C3 haloalkyl;   wherein each of R 2a , R 2b , R 2c , and R 2d  is independently selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 alkylamino, and (C1-C3)(C1-C3) dialkylamino; and   wherein R 4 , when present, is selected from hydrogen and C1-C3 alkyl.   
     
     
         6 . The method of  claim 1 , wherein the compound has a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The method of  claim 1 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The method of  claim 1 , wherein the disease is necrotizing enteritis. 
     
     
         9 . The method of  claim 1 , wherein the subject is a farm animal. 
     
     
         10 . The method of  claim 9 , wherein the farm animal is selected from a chicken, a turkey, a goose, a duck, a cow, a sheep, a horse, and a pig. 
     
     
         11 . A method for inhibiting germination of at least one  Clostridium perfringens  spore, the method comprising contacting the spore with a compound having a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein Q is selected from O, S, and Me;
 wherein R 3 , when present, is selected from hydrogen and C1-C8 alkyl; 
 
         wherein Z is selected from O, S, and NR 4 ;
 wherein R 4 , when present, is selected from hydrogen and C1-C8 alkyl; 
 
         wherein R 1  is selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, —CR 5a R 5b (C═O)NHN═CR 6 Ar 1 , Cy 1 , and Ar 2 , provided that if Q is NR 3  then R 1  is not —CR 5a R 5b (C═O)R 5 ;
 wherein each of R 5a  and R 5b , when present, is independently selected from hydrogen and C1-C4 alkyl; 
 wherein R 6 , when present, is selected from hydrogen and C1-C4 alkyl; 
 wherein Cy 1  is selected from C3-C7 cycloalkyl and C2-C7 heterocycloalkyl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; 
 wherein Ar 1  is selected from aryl and heteroaryl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; 
 wherein Ar 2  is selected from aryl and heteroaryl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and 
 
         wherein each of R 2a , R 2b , R 2c , and R 2d  is independently selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, 
         thereby inhibiting germination of at least one  Clostridium perfringens  spore. 
       
     
     
         12 . The method of  claim 11 , wherein the spore is in the gut of an animal. 
     
     
         13 . The method of  claim 11 , wherein Z is selected from O and NR 4 ;
 wherein R 1  is selected from hydrogen, C1-C3 alkyl, and C1-C3 haloalkyl;   wherein each of R 2a , R 2b , R 2c , and R 2d  is independently selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 alkylamino, and (C1-C3)(C1-C3) dialkylamino; and   wherein R 4 , when present, is selected from hydrogen and C1-C3 alkyl.   
     
     
         14 . The method of  claim 11 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         15 . A feed composition comprising a feed component and a compound having a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein Q is selected from O, S, and NR 3 ;
 wherein R 3 , when present, is selected from hydrogen and C1-C8 alkyl; 
 
         wherein Z is selected from O, S, and NR 4 ;
 wherein R 4 , when present, is selected from hydrogen and C1-C8 alkyl; 
 
         wherein R 1  is selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, —CR 5a R 5b (C═O)NHN═CR 6 Ar 1 , Cy 1 , and Ar 2 , provided that if Q is NR 3  then R 1  is not —CR 5a R 5b (C═O)R 5 ;
 wherein each of R 5a  and R 5b , when present, is independently selected from hydrogen and C1-C4 alkyl; 
 wherein R 6 , when present, is selected from hydrogen and C1-C4 alkyl; 
 wherein Cy 1  is selected from C3-C7 cycloalkyl and C2-C7 heterocycloalkyl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; 
 wherein Ar 1  is selected from aryl and heteroaryl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; 
 wherein Ar 2  is selected from aryl and heteroaryl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and 
 
         wherein each of R 2a , R 2b , R 2c , and R 2d  is independently selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. 
       
     
     
         16 . The composition of  claim 15 , wherein the feed component is selected from a vegetable protein, a fat-soluble vitamin, a water soluble vitamin, a trace mineral, and a macro mineral. 
     
     
         17 . The composition of  claim 15 , wherein the composition is a granule. 
     
     
         18 . The composition of  claim 15 , wherein the composition is a pellet. 
     
     
         19 . The composition of  claim 15 , wherein the composition further comprises one or more of an antibiotic, an arsenical, an antioxidant, an antifungal, a probiotic, a flavoring agent, a binder, a pigment, a preservative, an emulsifier, and a sweetener. 
     
     
         20 . The composition of  claim 15 , wherein the compound is selected from: