Methods of treating mycobacterial infections using tetracycline compounds

1. A method of treating or preventing a mycobacterial infection in a subject in need thereof, said method comprising administering to said subject an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt or ester thereof, wherein said tetracycline compound is omadacycline represented by formula (5):

such that said mycobacterial infection in said subject is treated or prevented.

2. The method of claim 1 , wherein the mycobacterial infection is caused by a slow-growing mycobacterium.

3. The method of claim 2 , wherein the slow-growing mycobacterium belongs to Terrae clade, Triviale clade, Tuberculosis-Simiae clade, or a Mycobacterium tuberculosis complex (MTBC).

4. The method of claim 3 , wherein the slow-growing mycobacterium belongs to a mycobacterial species selected from the group consisting of the following species: M. terrae, M. algericus, M. arupensis, M. engbaekii, M. heraklionensis, M. hiberniae, M. icosiumassiliensis, M. kumamotonensis, M. longobardus, M. minnesotensis, M. nonchromogenicus, M. paraterrae, M. senuense, M. sinensis M. virginiensis, M. trivialis, M. koreensis and M. parakoreensis, M. tuberculosis, M. tuberculosis subsp. tuberculosis, M. africanum, M. alsense, M. angelicum, M. arosiense, M. asiaticum, M. avium, M. avium subsp. avium, M. avium subsp. paratuberculosis, M. avium subsp. silvaticum, M. avium subsp. hominissuis, M. bohemicum, M. botniense, M. bouchedurhonense, M. bourgelatii, M. bovis, M. bovis subsp. bovis, M. bovis subsp. caprae, M. branderi, M. canettii, M. caprae, M. celatum, M. chimaera, M. colombiense, M. conspicuum, M. cookii, M. europaeum, M. florentinum, M. fragae, M. gastri, M. genavsnse, M. gordonae, M. haemophiluseckshornense, M. heidelbergense, M. indicus pranii, M. interjectum, M. intermedium, M. intracellulare, M. kansasii, M. kubicae, M. kyorinense, M. lacus, M. lentiflavum, M. leprae, M. lepraemurium, M. lepromatosis, M. liflandii, M. malmoense, M. mantenii, M. marinum, M. marseillense, M. microti, M. monteriorense, M. mungi, M. nebraskense, M. novomagense, M. orygis, M. palustre, M. paraense, M. parraffinicum, M. paragordonae, M. paraintracellulare, M. parascrofulaceum, M. paraseculense, M. parmense, M. perscum, M. pinnipedii, M. pseudoshotsii, M. riyadhense, M. saskatchewanense, M. scrofulaceum, M. seculense, M. sherrisii, M. shimoidei, M. shinjukuense, M. shottsii, M. simiae, M. stomatepiae, M. szulgai, M. timonense, M. triplex, M. ulcerans, M. xenopi and M. yongonense, M. africanum, M. bovis, M. bovis BCG, M. canetti, M. caprae, M. microti, M. mungi, M. orygis, M. pinnipedii, M. suricattae and M. tuberculosis.

5. The method of claim 4 , wherein the slow-growing mycobacterium belongs to a mycobacterial species M. tuberculosis.

6. The method of claim 2 , wherein the slow-growing mycobacterium is a nontuberculous mycobacterium (NTM).

7. The method of claim 6 , wherein the NTM belongs to a Mycobacterium avium complex (MAC).

8. The method of claim 7 , wherein the NTM belongs to a mycobacterial species selected from the group consisting of the following species: M. avium, M. avium paratuberculosis, M. avium silvaticum, M. avium “hominissuis”, M. colombiense, M. chimaera, M. indicus pranii and M. intracellulare.

9. The method of claim 1 , wherein the mycobacterial infection is caused by a rapid-growing mycobacterium.

10. The method of claim 9 , wherein the rapid-growing mycobacterium is NTM.

11. The method of claim 9 , wherein the rapid-growing mycobacterium belongs to an Abscessus-Chelonae clade.

12. The method of claim 11 , wherein the rapid-growing mycobacterium belongs to a mycobacterial species selected from the group consisting of the following species: M. abscessus, M. abscessus subsp. abscessus, M. abscessus subsp. bolletii, M. abscessus subsp. massiliense, M. chelonae, M. chelonae subsp. chelonae, M. immunogenum, M. salmoniphilum, M. franklinii and M. saopaulense.

13. The method of claim 12 , wherein the rapid-growing mycobacterium belongs to a mycobacterial species M. abscessus.

14. The method of claim 12 , wherein the rapid-growing mycobacterium belongs to a mycobacterial species M. chelonae.

15. The method of claim 9 , wherein the rapid-growing mycobacterium belongs to a Fortuitum-Vaccae clade.

16. The method of claim 15 , wherein the rapid-growing mycobacterium belongs to a mycobacterial species selected from the group consisting of the following species: M. fortuitum, M. fortuitum subsp. fortuitum, M. fortuitum subsp. acetamidolyticum, M. acapulcense, M. agri, M. aichiense, M. alvei, M. anyangense, M. arabiense, M. arcueilence, M. aromaticivorans, M. aubagnense, M. aurum, M. austroafrinacum, M. bacteremicum, M. boenickei, M. brisnanense, M. brumae, M. canariasense, M. celeriflavum, M. chitae, M. chlorophenolicum, M. chubuense, M. conceprionense, M. confluentis, M. cosmeticum, M. crocinum, M. diernhoferi, M. doricum, M. duvalii, M. elephantis, M. fallax, M. facinogenes, M. flavescens, M. fluoranthenivorans, M. frederikspergense, M. gadium, M. gilvum, M. goodii, M. hassiacum, M. helvum, M. hippocampi, M. hodieri, M. holsaticum, M. houstonense, M. insubricum, M. iranicum, M. komanii, M. komossense, M. litorale, M. llatzerense, M. lutetiense, M. madagascariense, M. mageritense, M. malmesburyense, M. monacense, M. montmartrense, M. moriokaense, M. mucogenicum, M. murale, M. neoaurum, M. neworleansense, M. novocastrense, M. obuense, M. oryzae, M. pallens, M. parafortuitum, M. peregrinum, M. phlei, M. phocaicum, M. porcinum, M. ponferae, M. psychrotolerans, M. pulvens, M. pyrenivorans, M. rhodesiae, M. rufum, M. rutilum, M. sarraceniae, M. sediminis, M. senegalense, M. septicum, M. setense, M. smegmatis, M. sphagni, M. thermoresistibile, M. tokaiense, M. tusciae, M. vaccae, M. vanbaalenii, M. vulneris and M. wolinskyi.

17. The method of claim 16 , wherein the rapid-growing mycobacterium belongs to a mycobacterial species M. fortuitum.

18. The method of claim 1 , wherein the mycobacterial infection is in the lungs of the subject.

19. The method of claim 18 , wherein the subject additionally has a disease of the lungs or has undergone lung transplantation.

20. The method of claim 1 , wherein the mycobacterial infection is:

in a lymph node of the subject; or

an osteoarticular infection; or

a skin or a soft tissue infection (SSTI); or

involves a foreign object disposed in the subject.

21. The method of claim 20 , wherein the foreign object is selected from the group consisting of a medical device, an implant and a tattoo ink.

22. A method of treating or preventing a mycobacterial disease in a subject in need thereof, said method comprising administering to said subject an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt or ester thereof, wherein said tetracycline compound is omadacycline represented by formula (5):

such that said mycobacterial disease in said subject is treated or prevented.

23. A method of controlling or reducing the advancement, severity or effects of a mycobacterial disease in a subject in need thereof, said method comprising administering to said subject an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt or ester thereof, wherein said tetracycline compound is omadacycline represented by formula (5):

such that said mycobacterial disease in said subject is controlled, or the advancement, severity or effects of said mycobacterial disease in said subject are reduced.

24. The method of claim 22 , wherein said mycobacterial disease is caused by an infection with a slow-growing mycobacterium.

25. The method of claim 24 , wherein the slow-growing mycobacterium belongs to a Mycobacterium tuberculosis complex (MTBC).

26. The method of claim 24 , wherein the slow-growing mycobacterium belongs to a mycobacterial species M. tuberculosis.

27. The method of claim 26 , wherein said mycobacterial disease is tuberculosis.

28. The method of claim 22 , wherein said mycobacterial disease is caused by an infection with a rapid-growing mycobacterium.

29. The method of claim 22 , wherein said mycobacterial disease is caused by an infection with NTM.

30. The method of claim 29 , wherein said NTM belongs to a mycobacterial species selected from the group consisting of the following species: M. avium, M. kansasii, M. scrofulaceum, M. xenopi, M. simiae, M. habana, M. szulgai, M. fortuitum, M. vaccae, M. malmoense, M. heckeshornense, M. chelonae and M. abscessus.

31. The method of claim 30 , wherein said NTM belongs to a mycobacterial species selected from the group consisting of the following species: M. abscessus, M. chelonae and M. fortuitum.

32. The method of claim 22 , wherein said mycobacterial disease is selected from the group consisting of tuberculosis, leprosy, a pulmonary disease, lymphadenitis, a skin disease, an eye disease, a soft tissue disease, a bone disease, a fish tank granuloma and a Buruli ulcer.

33. The method of claim 32 , wherein said pulmonary disease is selected from the group consisting of bronchiectasis and pulmonary infection.

34. The method of claim 22 , wherein said mycobacterial disease is associated with a mycobacterial infection in a lymph node, a joint, a bone, a skin, a soft tissue of the subject.

35. The method of claim 22 , wherein said mycobacterial disease is associated with a mycobacterial infection involving a foreign object disposed in the subject.

36. A method of treating or preventing a mycobacterial infection in a subject in need thereof, said method comprising administering to said subject an effective amount of a tetracycline compound, or a pharmaceutically acceptable salt or ester thereof, wherein said tetracycline compound is omadacycline represented by formula (5):

wherein said mycobacterial infection is caused by a nontuberculous mycobacterium (NTM).

37. The method of claim 36 , wherein the NTM is a slow-growing mycobacterium.

38. The method of claim 37 , wherein the NTM belongs to a Mycobacterium avium complex (MAC).

39. The method of claim 36 , wherein the NTM is a rapid-growing mycobacterium.

40. The method of claim 39 , wherein the NTM belongs to a mycobacterial species selected from the group consisting of the following species: M. abscessus, M. chelonae and M. fortuitum.

41. The method of claim 1 , wherein said tetracycline compound is administered as a monotherapy.

42. The method of claim 1 , wherein said tetracycline compound is administered in combination with at least one additional anti-mycobacterial agent.

43. The method of claim 42 , wherein said at least one additional anti-mycobacterial agent is selected from the group consisting of diarylquinolone, rifapentine, rifalazil, a nitroimidazole, a benzothiazinone, capreomycin, clofazimine, cycloserine, dapsone, a thiocarbamide, ethambutol, DC-159a, a nitrobenzthiazole, sutezolid (PNU-100480), AZD-5847, posizolid (AZD-2563), para-aminosalicylic acid, SQ-109, SQ-609, a capuramycin, a caprazene nucleoside, an isothiazoloquinolone, thioridazine, thiacetazone, dirithromycin, roxithromycin, telithromycin, azithromycin, clarithromycin, erythromycin, amikacin, kanamycin, streptomycin, levofloxacin, moxifloxacin, gatifloxacin, linezolid, rifalazil, imipenem, meropenem, clavulanate and isoniazid.