BENZOXABOROLE COMPOUNDS AND USES THEREOF
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.
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 .