Novel Combinations of DNAK Inhibitors With Known Antibacterial Agents

Abstract

Compositions, methods and kits are provided comprising (a) a therapeutically effective amount of a DnaK inhibitor; and (b) a therapeutically effective amount of a known antibacterial agent. Such compositions, methods and kits are useful in the treatment of various bacterial infections.

1 . A method for treating a bacterial infection comprising coadministering to a patient in need of such treatment
 (a) a therapeutically effective amount of a DnaK inhibitor; and   (b) a therapeutically effective amount of a known antibacterial agent.   
     
     
         2 . The method of  claim 1 , wherein the DnaK inhibitor is pyrrhocoricin, drosocin or an analog thereof. 
     
     
         3 . The method of  claim 2 , wherein the known antibacterial agent is a member of the fluoroquinolone, β-lactam, tetracycline, macrolide, aminoglycoside, glycopeptide, or folic acid synthesis inhibitor family of antibiotics. 
     
     
         4 . The method of  claim 3 , wherein the DnaK inhibitor is an analog of pyrrhocoricin having the formula R 1 -SEQ ID NO: 1-R 2 ,
 wherein SEQ ID NO: 1 is Asp-Lys-Gly-Ser-Tyr-Leu-Pro-Arg-Pro-Thr-Pro-Pro-Arg-Pro-Ile-Tyr-Asn-R 3 -,   R 1  adds a net positive charge to the N-terminus of said peptide and is selected from the group consisting of
 (a) a straight chain, branched, cyclic or heterocyclic alkyl group; 
 (b) a straight chain, branched, cyclic or heterocyclic alkanoyl group; 
 (c) a positively charged reporter group; 
 (d) a sequence of additional amino acids selected from the group consisting of Arg-Val, Lys-Val, Val and Lys-Val-Asp-Lys-Val (SEQ ID NO: 2), 1-amino-1-carboxycyclohexane and 4-amino-4-carboxypiperidine, wherein the N-terminal additional amino acid is optionally substituted by one or more of (a), (b), or (c); and 
 (e) an additional amino acid sequence Arg-Pro-Pro-Thr-Pro-Arg-Pro-Leu-Lys-Val (SEQ ID NO: 3) that cyclizes the peptide by bridging between the N- and C-termini thereof, 
   R 2  is selected from the group consisting of
 (a) a free hydroxyl, an amide, an imide, or a sugar; and 
 (b) an additional amino acid selected from the group consisting of Asn, D-Asn, Asp, Asn substituted by a member selected from the group consisting of a free hydroxyl, an amide, an imide, and a sugar, and Asp substituted by a member selected from the group consisting of a free hydroxyl, an amide, an imide and a sugar, and 
   R 3  is selected from the group consisting of arginine or N-alkylarginine, wherein alkyl represents a 1-6 carbon saturated chain.   
     
     
         5 . The method of  claim 4 , wherein R 2  is Asn-R 4 ,
 R 4  is selected from the group consisting of
 (a) a free hydroxyl, an amide, an imide, or a sugar; and 
 (b) a substituted amino acid represented by structural formula I 
   
       
         
           
           
               
               
           
         
         R 5  is selected from alkanoyl, aroyl or arylalkanoyl, R 6  is hydrogen or alkyl and n=1-4. 
       
     
     
         6 . The method of  claim 5 , wherein R 1  is selected from the group consisting of valine, 1-amino-1-carboxycyclohexane, 4-amino-4-carboxypiperidine, R 3  is selected from the group consisting of arginine and N-alkylarginine, R 4  is a substituted amino acid represented by structural formula I 
       
         
           
           
               
               
           
         
         R 5  is selected from the group consisting of acetyl and R 1 -SEQ ID NO: 1-R 2 , R 6  is hydrogen and n=1 or 2. 
       
     
     
         7 . The method of  claim 6 , wherein the DnaK inhibitor is CHP-105. 
     
     
         8 . The method of  claim 4  or  7 , wherein the DnaK inhibitor and the known antibacterial agent are administered substantially simultaneously. 
     
     
         9 . The method of  claim 4  or  7 , wherein the DnaK inhibitor and the known antibacterial agent are administered sequentially. 
     
     
         10 . The method of  claim 4  or  7 , wherein the coadministration enhances the therapeutic effect of the DnaK inhibitor, the known antibacterial agent or both. 
     
     
         11 . The method of  claim 4  or  7 , wherein the enhancement is synergistic. 
     
     
         12 . The method of  claim 4  or  7 , wherein the coadministration reduces the effective therapeutic dose of the known antibacterial agent. 
     
     
         13 . The method of  claim 4  or  7 , wherein the coadministration increases the spectrum of activity of the known antibacterial agent. 
     
     
         14 . The method of  claim 4  or  7 , wherein the coadministration reduces the incidence of resistance to the known antibacterial agent. 
     
     
         15 . The method of  claim 4  or  7 , wherein the coadministration extends the duration of activity of the known antibacterial agent. 
     
     
         16 . A pharmaceutical composition for treating a bacterial infection, comprising:
 (a) a therapeutically effective amount of a DnaK inhibitor; and   (b) a therapeutically effective amount of a known antibacterial agent.   
     
     
         17 . The composition of  claim 16 , wherein the DnaK inhibitor is pyrrhocoricin, drosocin or an analog thereof. 
     
     
         18 . The composition of  claim 17 , wherein the known antibacterial agent is a member of the fluoroquinolone, β-lactam, tetracycline, macrolide, aminoglycoside, glycopeptide, or folic acid synthesis inhibitor family of antibiotics. 
     
     
         19 . A kit for treating a bacterial infection comprising a container comprising:
 (a) a therapeutically effective amount of a DnaK inhibitor; and   (b) a therapeutically effective amount of a known antibacterial agent.   
     
     
         20 . The kit of  claim 19 , wherein the DnaK inhibitor is pyrrhocoricin, drosocin or an analog thereof. 
     
     
         21 . The kit of  claim 20 , wherein the known antibacterial agent is a member of the fluoroquinolone, β-lactam, tetracycline, macrolide, aminoglycoside, glycopeptide, or folic acid synthesis inhibitor family of antibiotics.