Modulation of Bacterial Quorum Sensing with Synthetic Ligands

Abstract

The present invention provides compounds and methods for modulation of the quorum sensing of bacteria. In an embodiment, the compounds of the present invention are able to act as replacements for naturally occurring bacterial quorum sensing ligands in a ligand-protein binding system; that is, they imitate the effect of natural ligands and produce an agonistic effect. In another embodiment, the compounds of the present invention are able to act in a manner which disturbs or inhibits the naturally occurring ligand-protein binding system in quorum sensing bacteria; that is, they produce an antagonistic effect. The compounds of the present invention comprise N-acylated-homoserine lactones (AHLs) comprised of a wide range of acyl groups.

We claim: 
     
         1 . A compound of formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or ester thereof, 
         wherein m is 1, 2, 3, or 4; 
         each R 1 , R 2 , and R 3  is independently selected from the group consisting of —R, —COOR, —COR, —CON(R) 2 , —OCON(R) 2 , —N(R) 2 , —SR, —SO 2 R, —SOR, —OCOOR, —SO 2 N(R) 2 , and —OR; wherein R is selected from the group consisting of a hydrogen, a halogen, an amine group, a substituted or unsubstituted unbranched C 1 -C 12  acyclic aliphatic group, a substituted or unsubstituted branched C 1 -C 12  acyclic aliphatic group, a substituted or unsubstituted C 3 -C 8  cycloalkyl group, a substituted or unsubstituted C 3 -C 8  cycloalkenyl group, a fluorinated C 1 -C 12  alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocycle, a substituted or unsubstituted C 1 -C 12  alkoxy group, a fluorinated C 1 -C 12  alkoxy group, a hydroxyl group, a nitrile group, an azide group, a nitro group, an acyl group, a thiol group, and a protecting group; additionally, R and R can form a ring; 
         X is S; 
         Y is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         L is 
       
       
         
           
           
               
               
           
         
         wherein one or more CH 2  groups may be replaced by NH, O, S, a carbonyl (C═O), or a sulfonyl (S═O or O═S═O); two adjacent CH 2  groups may be replaced by —CH═CH— or —C≡C—; and wherein p is selected from the range of 0 to 15; 
         Z is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         and n is 0 or 1; and 
         A is selected from the group consisting of an aryl group, a C 5 -C 8  cycloalkyl group, a C 5 -C 8  cycloalkenyl group, a heterocycle having a ring size of 5 to 8 atoms with 1, 2, or 3 hetereoatoms in the ring, an unbranched C 1 -C 12  acyclic aliphatic group, or a branched C 1 -C 12  acyclic aliphatic group, all of which may have one or more substituents selected from the group consisting of —R, —COOR, —COR, —CON(R) 2 , —OCON(R) 2 , —N(R) 2 , —SR, —SO 2 R, —SOR, —OCOOR, —SO 2 N(R) 2 , and —OR; wherein R is selected from the group consisting of a hydrogen, a halogen, an amine group, a substituted or unsubstituted unbranched C 1 -C 12  acyclic aliphatic group, a substituted or unsubstituted branched C 1 -C 12  acyclic aliphatic group, a substituted or unsubstituted C 3 -C 8  cycloalkyl group, a substituted or unsubstituted C 3 -C 8  cycloalkenyl group, a fluorinated C 1 -C 12  alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocycle, a substituted or unsubstituted C 1 -C 12  alkoxy group, a fluorinated C 1 -C 12  alkoxy group, a hydroxyl group, a nitrile group, an azide group, a nitro group, an acyl group, a thiol group, and a protecting group; additionally, R and R can form a ring. 
       
     
     
         2 . The compound of  claim 1 , wherein each R 1 , each R 2 , and R 3  are H. 
     
     
         3 . The compound of  claim 1 , wherein A is selected from the group consisting of a substituted aryl group, an unsubstituted aryl group, a substituted C 5 -C 8  cycloalkyl group, and an unsubstituted C 5 -C 8  cycloalkyl group. 
     
     
         4 . The compound of  claim 3 , wherein A is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 19  are each independently selected from the group consisting of hydrogen, —R, —COOR, —COR, —CON(R) 2 , —OCON(R) 2 , —N(R) 2 , —SR, —SO 2 R, —SOR, —OCOOR, —SO 2 N(R) 2 , and —OR, 
         wherein R is selected from the group consisting of, a halogen, an amine group, a substituted or unsubstituted unbranched C 1 -C 12  acyclic aliphatic group, a substituted or unsubstituted branched C 1 -C 12  acyclic aliphatic group, a substituted or unsubstituted C 3 -C 8  cycloalkyl group, a substituted or unsubstituted C 3 -C 8  cycloalkenyl group, a fluorinated C 1 -C 12  alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocycle, a substituted or unsubstituted C 1 -C 12  alkoxy group, a fluorinated C 1 -C 12  alkoxy group, a hydroxyl group, a nitrile group, an azide group, a nitro group, an acyl group, a thiol group, and a protecting group; or two R groups can form a ring. 
       
     
     
         5 . The compound of  claim 4 , wherein A is a substituted aryl group. 
     
     
         6 . The compound of  claim 5 , wherein A is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 4 , wherein A is a halogen or nitrile substituted aryl group. 
     
     
         8 . The compound of  claim 7 , wherein A is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 4 , wherein A is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 4 , wherein A is a hydroxyl, thiol, or alkoxy substituted aryl group. 
     
     
         11 . The compound of  claim 10 , wherein A is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         12 . The compound of  claim 4 , wherein A is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         13 . The compound of  claim 4 , wherein, in the compound having the formula FX1, A is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 1 , wherein A is a substituted or unsubstituted heterocycle having a ring size of 5 to 8 atoms with 1, 2, or 3 hetereoatoms in the ring. 
     
     
         15 . The compound of  claim 14 , wherein A is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         16 . The compound of  claim 1 , wherein A is selected from the group consisting of a fluorinated unbranched C 1 -C 12  acyclic aliphatic group, and a fluorinated branched C 1 -C 12  acyclic aliphatic group. 
     
     
         17 . The compound of  claim 1 , wherein m is 1. 
     
     
         18 . The compound of  claim 1 , wherein Y is 
       
         
           
           
               
               
           
         
       
     
     
         19 . The compound of  claim 1 , wherein L is 0, 1, 2 or 3. 
     
     
         20 . The compound of  claim 1 , wherein n is 0. 
     
     
         21 . The compound of  claim 1 , wherein n is 1. 
     
     
         22 . The compound of  claim 1 , wherein n is 1 and Z is 
       
         
           
           
               
               
           
         
       
     
     
         23 . The compound of  claim 1 , wherein:
 (1) when X is S, m is 1 and Y is CO, A-[Z] n -L- is a group other than a phenyl, a —CH 2 -phenyl, a —(CH 2 ) 2 -phenyl, —CH 2 —CH(CH 3 )-phenyl, —CH 2 —O-phenyl, —(CH 2 )—CO-phenyl, —(CH 2 )—NH-phenyl, —(CH 2 )—S-phenyl, —(CH 2 )—SO-phenyl, or a —(CH 2 )—SO 2 -phenyl;   (2) when X is S, m is 1 and Y is CO, A-[Z] n -L- is a group other than a -cyclohexyl group, a —CH 2 -cyclohexyl, or a —(CH 2 ) 2 -cyclohexyl; or   (3) when X is S, m is 1 and Y is CO, A-[Z] n -L- is a group other than a pyridine or a dithiane.   
     
     
         24 . A method for treating a bacterial infection in a subject comprising the step of administering an effective amount of a compound of  claim 1  to a subject in need of such treatment. 
     
     
         25 . The method of  claim 24 , wherein said bacteria is of a genus selected from the group consisting of  Aeromonas, Agrobacterium, Burkholderia, Chromobacterium, Enterobacter, Erwinia, Escherichia, Nitrosomas, Obesumbacterium, Pantoea, Pseudomonas, Ralstonia, Rhisobium, Rhodobacter, Serratia, Vibrio, Xenorhabdus , and  Yersinia.    
     
     
         26 . The method of  claim 24 , wherein said bacteria is of a species selected from the group consisting of  Aeromonas hydrophila, Aeromonas salmonicida, Agrobacterium tumefaciens, Burkholderia cepacia, Chromobacterium violaceum, Enterobacter agglomeran, Erwinia carotovora, Erwinia chrysanthemi, Escherichia coli, Nitrosomas europaea, Obesumbacterium proteus, Pantoea stewartii, Pseudomonas aureofaciens, Pseudomonas aeruginosa, Pseudomonas syringae, Ralstonia solanacearum, Rhisobium etli, Rhisobium leguminosarum, Rhodobacter sphaeroides, Serratia liguefaciens, Serratia marcescens, Vibrio anguillarum, Vibrio fischeri, Vibrio cholerae, Xenorhabdus nematophilus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia medievalis , and  Yersinia ruckeri.