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.

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, haloalkyl 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 - 20 . (canceled) 
     
     
         21 . A compound of formula: 
       
         
           
           
               
               
           
         
         or salts thereof where: 
         L is —CH 2 —X—CO—, where X is, S, O or NH; 
         R 1  and R 2  are iso-butyl groups; 
         R 3  is an optionally substituted phenyl or an optionally substituted benzyl group; 
         R 4  is selected from a C1-C3 alkyl group or a —CH 2 —COOH group; 
         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; 
         R 6  and R 7  are hydrogens; and 
         R 8 , R 9 , R 10  and R 14  are each selected from hydrogen or a methyl group, wherein one of R 8 , R 9 , R 10  or R 14  is a methyl group, 
         wherein optional substitution is substitution with one or more halogens, hydroxyl groups or alkyl groups having 1-3 carbon atoms; and 
         wherein each amino acid is an L-amino acid. 
       
     
     
         22 . A compound of formula: 
       
         
           
           
               
               
           
         
         or salts thereof where: 
         L is —CH 2 —X—CO—, where X is, S, O or NH; 
         R 1  and R 2  are iso-butyl groups; 
         R 3  is an optionally substituted phenyl or an optionally substituted benzyl group; 
         R 4  is selected from a C1-C3 alkyl group or a —CH 2 —COOH group; 
         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; 
         R 6 , R 7 , R 8 , R 9 , R 10  are hydrogens; and 
         R 14  is a methyl group, 
         wherein optional substitution is substitution with one or more halogens, hydroxyl groups or alkyl groups having 1-3 carbon atoms; and 
         wherein each amino acid is an L-amino acid. 
       
     
     
         23 . The compound or salt of  claim 22 , wherein L is —CH 2 —SCO—. 
     
     
         24 . The compound or salt of  claim 22 , wherein R 3  is an optionally substituted benzyl group. 
     
     
         25 . The compound or salt of  claim 22 , wherein R 4  is a —CH 2 —COOH group. 
     
     
         26 . The compound or salt of  claim 22 , wherein R 12  is a —CH 2 —CO—NH 2  group. 
     
     
         27 . The compound or salt of  claim 22 , wherein R′ 12  is a sec-butyl group. 
     
     
         28 . The compound or salt of  claim 22 , wherein R′ 12  is a C4 alkyl group. 
     
     
         29 . The compound or salt of  claim 22  which is I—NMeN—(CDFLL) or a salt thereof. 
     
     
         30 . A pharmaceutical composition which comprises a therapeutically effective amount of one or more compounds or salts of  claim 21  and a pharmaceutically acceptable carrier. 
     
     
         31 . A method for regulating virulence in  Staphylococcus  which comprises the step of contacting the bacterium with one or more compounds or salts of  claim 21 . 
     
     
         32 . The method of  claim 31  for attenuating virulence in a strain of  Staphylococcus.    
     
     
         33 . The method of  claim 32  wherein the production of toxic shock syndrome toxin-1 is attenuated. 
     
     
         34 . 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 21 . 
     
     
         35 . The method of  claim 34  wherein the staphylococcal infection is a  Staphylococcus aureus  infection.