Methods to inhibit intracellular growth of bacteria and to treat bacteria-mediated diseases

A method of increasing the acidity of bacterial phagosomes to inhibit mycobacterial growth in a cell, the method comprising contacting the cell with at least one of the compounds selected from the group consisting of:

• N,N-dimethyl imidodicarbonimidic diamide hydrochloride (Metformin);
• 3,5,4′-trihydroxy-trans-stilbene (Resveratrol);
• methyl 2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-1,4-dihydropyridine-3-carboxylate (Bay K8644);
• 2,5-Dimethyl-4-[2-(phenylmethyl)benzoyl]-1H-pyrrole-3-carboxylic acid methyl ester (FPL 64176);
• 2′,5′-Dideoxyadenosine;
• 4-14-(4-chlorophenyl)-4-hydroxypiperidin-1-yl1-N,N-dimethyl-2,2-diphenylbutanamide hydrochloride (Loperamide);
• (5R,6S,8S)-Hexyl 6-hydroxy-5-methyl-13-oxo-6,7,8,13,14,15-hexahydro-5H-16-oxa-4b,8a,14-triaza-5,8-methanodibenzo[b,h]cycloocta[jkl]cyclopenta[e]-as-indacene-6-carboxylate (KT 5720);
• N-(dicyclopropylmethyl)-4,5-dihydro-1,3-oxazol-2-amine (Rilmenidine);
• 3-(2-methoxyethyl) 5-propan-2-yl2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (Nimodipine);
• (RS)-ethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (Nitrendipine);
• (2-{4-[(2-butyl-1-benzofuran-3-yl)carbonyl]-2,6-diiodophenoxy}ethyl)diethylamine (Amiodarone);
• and
• [(2R,3S,4R,5R)-5-(4-Carbamoyl-5-aminoimidazol-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl dihydrogen phosphate (AICAR), wherein the method further comprises administration of an anti-tuberculosis drug, wherein the anti-tuberculosis drug is selected from the group consisting of isoniazid, pyrazinamide, rifampicin, ethionamide, rifabutin, amikacin, ethambutol, PA824, bedaquiline, streptomycin, kanamycin, and fluoroquinolone antibiotic or a combination thereof.

A method of increasing mitochondrial reactive oxygen species (mROS) generation to inhibit mycobacterial growth in a cell, the method comprising contacting the cell with at least one of the compounds selected from the group consisting of:

• N,N-dimethyl imidodicarbonimidic diamide hydrochloride (Metformin);
• 3,5,4′-trihydroxy-trans-stilbene (Resveratrol);
• methyl 2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-1,4-dihydropyridine-3-carboxylate (Bay K8644);
• 2,5-Dimethyl-4-[2-(phenylmethyl)benzoyl]-1H-pyrrole-3-carboxylic acid methyl ester (FPL 64176);
• 2′,5′-Dideoxyadenosine;
• 4-14-(4-chlorophenyl)-4-hydroxypiperidin-1-yl1-N,N-dimethyl-2,2-diphenylbutanamide hydrochloride (Loperamide);
• (5R,6S,8S)-Hexyl 6-hydroxy-5-methyl-13-oxo-6,7,8,13,14,15-hexahydro-5H-16-oxa-4b,8a,14-triaza-5,8-methanodibenzo[b,h]cycloocta[jkl]cyclopenta[e]-as-indacene-6-carboxylate (KT 5720);
• N-(dicyclopropylmethyl)-4,5-dihydro-1,3-oxazol-2-amine (Rilmenidine);
• 3-(2-methoxyethyl) 5-propan-2-yl2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (Nimodipine);
• (RS)-ethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (Nitrendipine);
• (2-{4-[(2-butyl-1-benzofuran-3-yl)carbonyl]-2,6-diiodophenoxy}ethyl)diethylamine (Amiodarone);
• and
• [(2R,3S,4R,5R)-5-(4-Carbamoyl-5-aminoimidazol-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl dihydrogen phosphate (AICAR), wherein the method further comprises administration of an anti-tuberculosis drug, wherein the anti-tuberculosis drug is selected from the group consisting of isoniazid, pyrazinamide, rifampicin, ethionamide, rifabutin, amikacin, ethambutol, PA824, bedaquiline, streptomycin, kanamycin, and fluoroquinolone antibiotic or a combination thereof.

A pharmaceutical composition comprising:

• at least one of the compounds selected from the group consisting of:
• N,N-dimethyl imidodicarbonimidic diamide hydrochloride (Metformin);
• methyl 2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-1,4-dihydropyridine-3-carboxylate (Bay K8644);
• 2,5-Dimethyl-4-[2-(phenylmethyl)benzoyl]-1H-pyrrole-3-carboxylic acid methyl ester (FPL 64176);
• 2′,5′-Dideoxyadenosine;
• 4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-N,N-dimethyl-2,2-diphenylbutanamide hydrochloride (Loperamide);
• (5R,6S,8S)-Hexyl 6-hydroxy-5-methyl-13-oxo-6,7,8,13,14,15-hexahydro-5H-16-oxa-4b,8a,14-triaza-5,8-methanodibenzo[b,h]cycloocta[jkl]cyclopenta[e]-as-indacene-6-carboxylate (KT 5720);
• N-(dicyclopropylmethyl)-4,5-dihydro-1,3-oxazol-2-amine (Rilmenidine);
• 3-(2-methoxyethyl) 5-propan-2-yl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (Nimodipine);
• (RS)-ethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (Nitrendipine);
• (2-{4-[(2-butyl-1-benzofuran-3-yl)carbonyl]-2,6-diiodophenoxy}ethyl)diethylamine (Amiodarone);
• and
• [(2R,3S,4R,5R)-5-(4-Carbamoyl-5-aminoimidazol-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl dihydrogen phosphate (AICAR);
• and
• an anti-tuberculosis drug selected from the group consisting of isoniazid, pyrazinamide, rifampicin, ethionamide, rifabutin, amikacin, ethambutol, PA824, bedaquiline, streptomycin, kanamycin, and fluoroquinolone antibiotic or a combination thereof.

A method for eliciting an immune response to an intracellular mycobacteria, said method comprising administering at least one compound selected from the group consisting of:

• N,N-dimethyl imidodicarbonimidic diamide hydrochloride (Metformin);
• 3,5,4′-trihydroxy-trans-stilbene (Resveratrol);
• methyl 2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-1,4-dihydropyridine-3-carboxylate (Bay K8644);
• 2,5-Dimethyl-4-[2-(phenylmethyl)benzoyl]-1H-pyrrole-3-carboxylic acid methyl ester (FPL 64176);
• 2′,5′-Dideoxyadenosine;
• 4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-N,N-dimethyl-2,2-diphenylbutanamide hydrochloride (Loperamide);
• (5R,6S,8S)-Hexyl 6-hydroxy-5-methyl-13-oxo-6,7,8,13,14,15-hexahydro-5H-16-oxa-4b,8a,14-triaza-5,8-methanodibenzo[b,h]cycloocta[jkl]cyclopenta[e]-as-indacene-6-carboxylate (KT 5720);
• N-(dicyclopropylmethyl)-4,5-dihydro-1,3-oxazol-2-amine (Rilmenidine);
• 3-(2-methoxyethyl) 5-propan-2-yl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (Nimodipine);
• (RS)-ethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (Nitrendipine);
• (2-{4-[(2-butyl-1-benzofuran-3-yl)carbonyl]-2,6-diiodophenoxy}ethyl)diethylamine (Amiodarone);
• and
• [(2R,3S,4R,5R)-5-(4-Carbamoyl-5-aminoimidazol-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl dihydrogen phosphate (AICAR), wherein the method further comprises administration of an antituberculosis drug, wherein the anti-tuberculosis drug is selected from the group consisting of isoniazid, pyrazinamide, rifampicin, ethionamide, rifabutin, amikacin, ethambutol, PA824, bedaquiline, streptomycin, kanamycin, and fluoroquinolone antibiotic or a combination thereof.