Patent
The present invention is directed to methods and compounds for inhibiting bacterial growth and treating a bacterial infection in a subject. These methods involve providing an inhibitor of intrabacterial pH homeostasis, including inhibitors of the Mycobacterium tuberculosis Rv3671c gene encoded membrane protease. Methods for identifying novel compounds that disrupt intrabacterial pH homeostasis and their use for inhibiting bacterial growth and treating a bacterial infection in a subject are also disclosed.
1. A method of inhibiting growth of Mycobacterium comprising:
exposing Mycobacterium to an agent selected from the group consisting of 6-(3-butyryl-2,6-dihydroxy-4-methoxy-5-methylbenzyl)-3,5-dihydroxy-4,6-dimethyl-2-(2-methylbutanoyl)cyclohexa-2,4-dienone; (Z)-2-(3-hydroxy-5-oxo-4-pentylfuran-2(5H)-ylidene) acetic acid; 4-(2-methylbutanoyloxy)-5-(octanoyloxy)-2-((3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)methyl)-6-(2,3,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yloxy)tetrahydro2H-pyran-3-yl decanoate; 2-hydroxy-4-methoxy-3-(3-methylbut-2-enyl)-6-pentylbenzoic acid; and 2-hydroxy-3-(2-hydroxy-3-methylbut-3-enyl)-4-methoxy-6-phenethylbenzoic acid under conditions effective to disrupt intrabacterial pH homeostasis and inhibit growth of the Mycobacterium.
2. The method according to claim 1 , wherein said exposing is carried out under pH conditions that are different than that of the intrabacterial pH homeostatic conditions.
3. The method according to claim 2 , wherein said exposing is carried out under acidic pH conditions.
4. The method according to claim 1 , wherein the Mycobacterium is selected from the group consisting of Mycobacterium tuberculosis, Mycobacterium avium - intracellulare, Mycobacterium kansasii, Mycobacterium bovis, Mycobacterium bovis BCG, Mycobacterium africanum, Mycobacterium canetti, Mycobacterium caprae, Mycobacterium pinnipedii, Mycobacterium ulcerans , and Mycobacterium leprae.
5. The method according to claim 4 , wherein the Mycobacterium is Mycobacterium tuberculosis.
6. A method of treating a bacterial Mycobacterium infection in a subject comprising
administering to the subject an agent selected from the group consisting of 6-(3-butyryl-2,6-dihydroxy-4methoxy-5-methylbenzyl)-3,5-dihydroxy-4,6-dimethyl-2-(2-methylbutanoyl)cyclohexa-2,4-dienone; (Z)-2-(3-hydroxy-5-oxo-4-pentylfuran-2(5H)-ylidene)acetic acid; 4-(2-methylbutanoyloxy)-5-(octanoyloxy)-2-((3,4,5-trihydroxy-6-(hydroxymethyl) tetrahydro-2H-pyran-2-yloxy)methyl)-6-(2,3,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yloxy)tetrahydro2H-pyran-3-yl decanoate; 2-hydroxy-4-methoxy-3-(3-methylbut-2-enyl)-6-pentylbenzoic acid; and 2-hydroxy-3-(2-hydroxy-3-methylbut-3-enyl)-4-methoxy-6-phenethylbenzoic acid under conditions effective to disrupt intrabacterial pH homeostasis and treat the Mycobacterium infection.
7. The method according to claim 6 further comprising
selecting a subject having a Mycobacterium infection prior to said administering.
8. The method according to claim 6 , wherein the Mycobacterium is selected from the group consisting of Mycobacterium tuberculosis, Mycobacterium avium - intracellulare, Mycobacterium kansasii, Mycobacterium bovis, Mycobacterium bovis BCG, Mycobacterium africanum, Mycobacterium canetti, Mycobacterium caprae, Mycobacterium pinnipedii, Mycobacterium ulcerans , and Mycobacterium leprae.
9. The method according to claim 8 , wherein the Mycobacterium is Mycobacterium tuberculosis.
10. The method according to claim 6 , wherein the agent is administered in combination with one or more antibacterial agents.
11. The method according to claim 10 , wherein the one or more antibacterial agents are selected from the group consisting of isoniazid, rifampin, rifabutin, rifapentine, pyrazinamide, and ethambutol.