Compositions and methods for inhibition of mycobacteria
A composition comprising a drug selected from the group consisting of an arylphenoxypropionate derivative, an aryloxyphenoxyacetate derivative, an aryloxyphenylacetate derivative, a substituted quinol, or a salt, hydrate, or prodrugs thereof, or a combination thereof, in an amount and formulation sufficient to inhibit a mycobacterium is disclosed.
1. A composition comprising:
a drug comprising 2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-N-methylpropanamide, 1-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-3-(propan-2-yl)urea, 1-{4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]phenyl}-3-(propan-2-yl)urea, or 2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-N-methoxypropanamide, or a pharmaceutically acceptable salt, hydrate, or prodrug thereof in an amount and formulation sufficient to inhibit a mycobacterium expressing Acetyl-CoA carboxyltransferase β-subunit D6 (AccD6); and
a pharmaceutically acceptable carrier.
2. The composition of claim 1 , further comprising a salt, a buffer, a preservative, or a solubility enhancer.
3. The composition of claim 1 , wherein the mycobacterium is Mycobacterium tuberculosis or Mycobacterium bovis.
4. A method of inhibiting a mycobacterium expressing Acetyl-CoA carboxyltransferase β-subunit D6 (AccD6) comprising:
administering a composition comprising a drug, having the formula:
wherein:
R 1 is selected from —OH, —OCH 3 , —NHOCH 3 , —NHCH 3 , and —NHCH(CH 3 ) 2 groups;
R 2 and R 3 are both H or at least one of R 2 and R 3 is —CH 3 ; and
R 4 is selected from a 1,3-benzothiazole-2-yl, 1,3-benzothiazole-2-yl substituted with a halogen or —OCH 3 group, and quinoxaline-2-yl, or a pharmaceutically acceptable salt, hydrate, or prodrug thereof to the mycobacterium in an amount and for a time sufficient to inhibit AccD6 in the mycobacterium.
5. The method of claim 4 , wherein the mycobacterium is pathogenic.
6. The method of claim 4 , wherein the mycobacterium is selected from the group consisting of Mycobacterium tuberculosis or Mycobacterium bovis.
7. The method of claim 4 , wherein the composition is substantially nontoxic to animals.
8. The method of claim 4 , wherein the mycobacterium is drug resistant.
9. The method of claim 4 , wherein the mycobacterium is multi-drug resistant.
10. The method of claim 4 , wherein the drug has a minimum inhibitory concentration for the mycobacterium of between 0.1 μM and 50 μM.
11. The method of claim 4 , wherein R 1 is selected from —OH, —OMe, —NHOCH 3 , —NHCH 3 , and —NHCH(CH 3 ) 2 groups;
R 2 and R 3 are both H or one of R 2 and R 3 is —CH 3 ; and
R 4 is 1,3-benzothiazole-2-yl.
12. The method of claim 4 , wherein the drug is 2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-N-methylpropanamide, 1-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-3-(propan-2-yl)urea, 1-{4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]phenyl}-3-(propan-2-yl)urea, or 2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-N-methoxypropanamide.
13. The method of claim 4 , wherein the drug has a minimum inhibitory concentration for the mycobacterium of between 0.3 μM and 20 μM.
14. The method of claim 4 , wherein the drug has a minimum inhibitory concentration for the mycobacterium of between 1 μM and 10 μM.
15. The method of claim 4 , wherein the drug has a minimum inhibitory concentration for the mycobacterium of between 1 μM and 25 μM.
16. The method of claim 4 , wherein the drug has a unit dosage of between 1 mg/kg body weight and 500 mg/kg body weight.
17. The method of claim 4 , wherein the drug has a unit dosage of between 5 mg/kg body weight to about 350 mg/kg body weight.
18. The method of claim 4 , wherein the drug has a unit dosage of between 0 mg/kg body weight and about 200 mg/kg body weight.