Benzoxaborole compounds and uses thereof

Abstract

Norvaline and/or other amino acids that are capable of being acylated onto tRNA Leu by LeuRS, in combination with substituted benzoxaboroles, such as a compound having a structure according to formula III: and methods for decreasing the frequency of resistance and/or reducing the rate of resistance and/or suppressing the emergence of resistance that develops in bacteria exposed to a substituted benzoxaborole or salt thereof by administering a combination of a substituted benzoxaborole such as a compound of formula III or salt thereof and an amino acid or a salt thereof.

What is claimed is: 
     
         1 . A combination of an amino acid or amino acid salt that is capable of being acylated onto tRNA Leu  by LeuRS and a compound having a structure according to formula II: 
       
         
           
           
               
               
           
         
         wherein R 3  is a member selected from H, cyano, substituted or unsubstituted nitroalkyl and substituted or unsubstituted aminoalkyl; R a  is a member selected from H and —YR 5 ; 
         wherein Y is a member selected from O and S; R 5  is a member selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl with the proviso that R a  and R3 cannot both be H; and with the proviso that when R 3  is H, R a  does not have a structure which is a member selected from: unsubstituted benzyloxy, —OCH 2 COOH, methoxy, ethoxy, with the proviso that when R a  is H, R 3  is not cyano, or a salt thereof. 
       
     
     
         2 . A combination of an amino acid or amino acid salt that is capable of being acylated onto tRNA Leu  by LeuRS and a compound having a structure according to formula III: 
       
         
           
           
               
               
           
         
         wherein the amino acid or amino acid salt is selected from the group consisting of allylglycine, norvaline, methionine, norleucine, isoleucine, homocysteine, homoserine, and valine, or a structural analog thereof that is capable of being acylated onto tRNA Leu  by LeuRS. 
       
     
     
         3 . A combination according to  claim 2 , wherein the compound is a compound of formula III and the amino acid or its salt is norvaline or a structural analog of norvaline. 
     
     
         4 . A combination according to  claim 1 , wherein the compound is a compound as indicated below 
       
         
           
           
               
               
           
         
         and the amino acid or amino acid salt is norvaline or a structural analog of norvaline. 
       
     
     
         5 . A method for decreasing the frequency of resistance and/or reducing the rate of resistance and/or suppressing the emergence of resistance that develops in bacteria exposed to a substituted benzoxaborole or salt thereof, comprising:
 administering to a subject having a bacterial infection a combination of a substituted compound of formula II or salt thereof and an amino acid or a salt thereof.   
     
     
         6 . A method for decreasing the frequency of resistance and/or reducing the rate of resistance and/or suppressing the emergence of resistance that develops in bacteria exposed to a substituted benzoxaborole or salt thereof, comprising:
 administering to a subject having a bacterial infection a combination of a substituted compound of formula III or salt thereof and an amino acid or a salt thereof.   
     
     
         7 . A method according to  claim 5  wherein the amino acid or salt thereof is selected from the group consisting of allylglycine, norvaline, methionine, norleucine, isoleucine, homocysteine, homoserine, and valine, or is selected from a structural analog thereof that is capable of being acylated onto tRNA Leu  by LeuRS. 
     
     
         8 . A method according to  claim 6  wherein the amino acid or salt thereof is selected from the group consisting of allylglycine, norvaline, methionine, norleucine, isoleucine, homocysteine, homoserine, and valine, or is selected from a structural analog thereof that is capable of being acylated onto tRNA Leu  by LeuRS. 
     
     
         9 . A method for treating a bacterial infection in a subject, comprising administering to the subject a combination of a combination according to  claim 1 . 
     
     
         10 . A method for treating a bacterial infection in a subject, comprising administering to the subject a combination of a combination according to  claim 2 . 
     
     
         11 . A method for treating a bacterial infection in a subject, comprising administering to the subject a combination of a combination according to  claim 5 . 
     
     
         12 . A method for treating a bacterial infection in a subject, comprising administering to the subject a combination of a combination according to  claim 1 .