Peptide-based quorum sensing inhibitors for the attenuation of virulence in staphylococcus aureus

Abstract

Compounds that affect quorum sensing (QS) in Staphylococcus aureus and related Staphylococcus species (e.g., S. epidermidis ). Compounds which modulate one or more of the four AgrC receptors of Staphylococcus species, particularly of Staphylococcus aureus . Modulation includes inhibition or activation of one or more of these four AgrC receptors. These compounds are useful for bacterial interference and are useful for treating bacterial infections, particularly staphylococcal infection. Treatment can include combination of one or more of the compounds of the invention in combination with one or more antibiotics.

We claim: 
     
         1 . A compound of formula: 
       
         
           
           
               
               
           
         
         or salts thereof where: 
         L is a divalent linker moiety 3 to 10 atoms in length; 
         Z is a divalent linker moiety 3 to 12 atoms in length; 
         R 1  and R 2  are independently selected from hydrogen, an optionally substituted alkyl group having 1-6 carbon atoms, an optionally substituted aryl group or an optionally substituted heteroaryl group; 
         R 6  and R 7  are independently selected from hydrogen, an optionally substituted alkyl group having 1-8 carbon atoms, an optionally substituted aryl group or an optionally substituted heteroaryl group; where, when R 1  is a group other than hydrogen or a methyl group, R 6  is a hydrogen or a methyl group and when R 2  is a group other than hydrogen or a methyl group, R 7  is a hydrogen or a methyl group; 
         R 10  is hydrogen or a methyl group; 
         R 5  is an optionally substituted alkyl group having 1-8 carbon atoms, an optionally substituted aryl group, an optionally substituted heteroaryl group or R 5  is: 
         H 2 N—CHR 12 —, H 2 N—CHR 12 —CO—NR 14 —, H 2 N—CHR 12 —CO—NR 14 —CHR 12 —, R 15 —CO—NR 14 —, or R 15 —CO—NR 14 —CHR 12 , where each R 12  is hydrogen, an optionally substituted alkyl group having 1-6 carbon atoms, an optionally substituted aryl group or an optionally substituted heteroaryl group; R 14  is hydrogen, an optionally substituted alkyl group having 1-8 carbon atoms, an optionally substituted aryl group or an optionally substituted heteroaryl group; and R 15  is an optionally substituted alkyl group having 1-8 carbon atoms, an optionally substituted aryl group or an optionally substituted heteroaryl group where, when R 5  is H 2 N—CHR 12 —CO—NR 14 — and R 12  is a group other than hydrogen or a methyl, R 14  is hydrogen or a methyl group; 
         wherein optional substitution is substitution with one or more substituents selected from the group consisting of halogen, hydroxyl group, nitro group, cyano group, isocyano group, oxo group, thioxo group, azide group, cyanate group, isocyanate group, acyl group, haloakyl group, alkyl group, alkenyl group, alkynyl group, phenyl group, benzyl group, halogen or alkyl substituted benzyl group, alkoxy group, alkylthio group, and mercapto group; and 
         wherein the compound is not AIP-I, AIP-II, AIP-III, AIP-IV, tAIP-1D2A or the cyclic thioester (C-A-F-L-L). 
       
     
     
         2 . The compound of  claim 1 , wherein L is
 —(CH 2 ) 1-4 —O—CO—, —(CH 2 ) 1-4 —NH—CO—, —(CH 2 ) 1-2 —O—(CH 2 ) 1-2 —CO—, (CH 2 ) 2-5 —CO—, —CO—(CH 2 ) 1-4 —CO—, or —CH 2 —NHCONH—CH 2 —.   
     
     
         3 . The compound of  claim 1 , wherein L is —CH 2 —X—CO—, where X is, S, O or NH. 
     
     
         4 . The compound of  claim 1 , wherein L is —CH 2 —NH—CO—. 
     
     
         5 . The compound of  claim 1 , wherein Z is selected from:
 —NR 9 —(CH 2 ) n —CO—NR 8 —CH(R 3 )—CO—; or   —NR 9 —CH(R 4 )—CO—NR 8 —CH(R 3 )—CO—,   wherein R 3  is hydrogen, an optionally substituted alkyl group having 1-6 carbon atoms, an optionally substituted aryl group, an optionally substituted heteroaryl group or an optionally substituted heterocyclic group;   R 4  is hydrogen, or an optionally substituted alkyl group having 1-3 carbon atoms;   R 9  and R 8  are independently selected from hydrogen, an optionally substituted alkyl group having 1-8 carbon atoms, an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted heterocyclic group; wherein when R 3  is a group other than hydrogen or a methyl group, R 8  is a hydrogen or a methyl group and when R 4  is a group other than hydrogen or a methyl group, R 9  is a hydrogen or a methyl group.   
     
     
         6 . The compound of  claim 5 , wherein Z is —NR 9 —CH(R 4 )—CO—NR 8 —CH(R 3 )—CO—. 
     
     
         7 . The compound of  claim 1  of formula: 
       
         
           
           
               
               
           
         
         or salts thereof, wherein each amino acid is an L-amino acid. 
       
     
     
         8 . The compound of  claim 7 , wherein R 6 , R 7  and R 8  are independently H or methyl, R 1  and R 2  are independently alkyl groups having 3 to 6 carbon atoms and R 3  is an optionally substituted benzyl group. 
     
     
         9 . The compound of  claim 8 , wherein R 5  is an alkyl group having 1-8 carbon atoms. 
     
     
         10 . The compound of  claim 9 , wherein R 5  is methyl, R 9  and R 10 , are independently H or methyl, R 3  is benzyl, and R 4  is C1-C3 alkyl. 
     
     
         11 . The compound of  claim 1  of formula: 
       
         
           
           
               
               
           
         
         or salts thereof where: 
         R 1  and R 2  are iso-butyl groups; 
         R 3  is a benzyl group; 
         R 4  is selected from a C1-C3 alkyl group or a —CH 2 —COOH group, and 
         R 12  and R′ 12  are independently selected from a C1-C4 alkyl group, a —CH 2 —CO—NH 2  group or a —CH 2 —CH 2 —CO—NH 2  group; and 
         wherein each amino acid is an L-amino acid. 
       
     
     
         12 . The compound of  claim 11  wherein R 9  and R 8  are independently selected from hydrogen, or an optionally substituted alkyl group having 1-8 carbon atoms. 
     
     
         13 . The compound of  claim 11  where R 4  is a C1-C3 alkyl group. 
     
     
         14 . A pharmaceutical composition which comprises a therapeutically effective amount of one or more compounds of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         15 . A method for regulating virulence in  Staphylococcus  which comprises the step of contacting the bacterium with one or more compounds selected from the compounds of  claim 1 . 
     
     
         16 . The method of  claim 15  for attenuating virulence in a strain of  Staphylococcus.    
     
     
         17 . The method of  claim 15  wherein the production of toxic shock syndrome toxin-1 is attenuated. 
     
     
         18 . A method of treating staphylococcal infection which comprises administering to an individual in need of treatment a therapeutically effective amount of one or more compounds of  claim 1 . 
     
     
         19 . The method of  claim 18  wherein the staphylococcal infection is a  Staphylococcus aureus  infection. 
     
     
         20 . The method of  claim 19  wherein the infection is toxic shock syndrome.