Table 1.

List of host specific FDA-approved drugs and inhibitors that were demonstrated in pre-clinical animal studies to have immunomodulatory activities decreasing the mycobacterial burden and dampening lung pathology (fold changes were extracted by using GetData Graph Digitizer).

HDT class	Drug	Brand name	Target mechanism	FDA approved disease target	Half-life (hours)	Mtb CFU reduction in animals	Lung pathology reduction in animals	Clinical trial	REF
MMP inhibitors	Marimastat	No brand name	Broad-spectrum MMP inhibitor	Not approved	8-10	1.1 log in mouse lungs INH vs INH + Marimastat	2.3 fold reduced consolidated lung regions	Not started	(9)
MMP inhibitors	Doxycycline	Vibramycin	Multiple MMP inhibitor	Bacterial infection	16	1.6 log in guinea pig lungs	reduced area of granulomatous involvement	Phase 2 NCT02774993	(10)
Antioxidants	N-acetylcysteine	No brand name	Antioxidants	Paracetamol overdose	5.6	1 log in guinea pig spleen	3 fold necrosis score reduction in lungs	Phase 2 NCT00564642	(11)
TNF blockers	Etanercept	Enbrel	Soluble TNFR fusion protein	Rheumatoid arthritis	101	3.5-7.5 fold in Kramnik mouse lungs RHZ vs RHZ+ Etanercept	2.5 fold reduced lung involvement RHZ vs RHZ+ Etanercept	Not started	(12)
Phosphodiesterase inhibitors	Sildenafil	Viagra Revatio	PDE-5 inhibitor	Erectile dysfunction Pulmonary arterial hypertension	3-5	RHZ + Sildenafil + Cilostazol decreased time to lung sterilization by 1 month in mice	1.4 fold fewer lung lesions	Not started	(13)
Phosphodiesterase inhibitors	Cilostazol	Pletal	PDE-3 inhibitor	Intermittent claudication	11-13	1.9 log in mouse lungs	1.8 fold fewer lung lesions RHZ vs RHZ + Cilostazol	Not started	(13)
Phosphodiesterase inhibitors	CC-3052	No brand name	PDE-4 inhibitor	Not approved	Not known	0.8 log in rabbit lungs INH vs INH + CC-3052	2.7 fold fewer lung lesions INH vs INH + CC-3052	Not started	(14)
Phosphodiesterase inhibitors	CC-11050	No brand name	PDE-4 inhibitor	Not approved	Not known	1 log in rabbit lungs INH vs INH + CC-11050	2 fold fewer subpleural lesions INH vs INH + CC-11050	Phase 2 NCT02968927	(15)
Histone deacetylases	Resveratrol	No brand name	Sirtuin-1 activator	Not approved	2-4	0.8 log in mouse lungs	1.1 fold reduced involvement of lung parenchyma	Not started	(16)
Histone deacetylases	SRT1720	No brand name	Sirtuin-1 activator	Not approved	Not known	0.5 log in mouse lungs	1.2 fold reduced involvement of lung parenchyma	Not started	(16)
Histone deacetylases	AGK2	No brand name	Sirtuin-2 inhibitor	Not approved	Not known	0.8 log in mouse lungs	granuloma score: 5 fold reduced	Not started	(17)
Autophagy inducer	Carbamazepine	Tegretol	Sodium channel blocker	Epilepsy	27-37	1.7 log in mouse lungs	reduced lung lesions scores by 1.4 fold	Not started	(18)
Nonsteroidal anti-inflammatory drugs	Ibuprofen	Brufen	COX-1 COX-2 inhibitors	Painkiller	1-2	1.2 log in Kramnik mouse lungs	3.8 fold reduction of total lung affected area	Phase 2 NCT02781909	(19)
Nonsteroidal anti-inflammatory drugs	Aspirin	Bayer Aspirin	COX-1 COX-2 inhibitors	Fever, pain, inflammation	0.25	1 log in mouse lungs	decreased lung pathology by 3 fold	Phase 2 NCT02237365	(20)
Anti-diabetic	Metformin	Glucophage	Mitochondrial ROS AMPK	Type 2 diabetes	4-8	0.4 log in mouse lungs	reduced pathological lung area by 2.6 fold	Phase 2 NCT04930744	(21)
Vitamins	Vitamin D	Cholecalciferol	Nutritional supplementation	Nutritional supplements	360	0.6 log in mouse lungs PZA vs PZA + Calcitriol	1.4 fold reduction in lung lesions PZA vs PZA + Calcitriol	Phase 3 NCT00419068	(22)
Vitamin A metabolite	All-trans retinoic acid (ATRA)	Altreno	Binds to nuclear receptors, retinoid x receptor and RAR-a	Cancer	0.5-2	1.9 log in mouse lungs 0.5 log in rat lungs	reduced lung lesions in rats but not quantified	Not started	(23, 24)
Tryptophan catabolism	1-methyl-tryptophan	NLG802	IDO inhibitor	Not approved	10.5	1.5 log in mouse lungs	2 fold reduction in lung involvement	Not started	(25)
Amino acid	L-isoleucine	Aminosyn II 7%	Defensin activator	Nutritional supplement	3.5	3.5 fold in mouse lungs	decreased pneumonic area by 3.4 fold	Not started	(26)
Lactate metabolism	FX11	No brand name	Lactate dehydrogenase A inhibitor	Not approved	Not known	0.7 log in mouse lungs	reduced lung necrotic lesions by 1.9 fold in NOS2-/- mice	Not started	(27)
Prostaglandins	Prostaglandin E2 (PGE2)	Cervidil	Regulates cellular responses to PGE2	Gestational Trophoblastic Disease	0.06	PGE2 + Zileuton 0.8 log in IL-1aIL-1b-/- and 2.1 log in pICLC-treated mouse bronchoalveolar lavage fluid	PGE2 + Zileuton 1.6 fold reduced lung inflamed areas in IL1R1 deficient mice and 1.4 fold in pICLC-treated mice	Not started	(28)
Iron binding	Zileuton	Zyflo	Catalyst in leukotriene biosynthesis	Asthma	2.5			Not started	(28)
Transmembrane signaling receptor	Anakinra	Kineret	Regulates cellular responses to IL-1a, IL-1b and IL-1RN	Idiopathic Recurrent Pericarditis	4-6	Anakira + Linezolid 0.4 log in lung macaques	Anakira + Linezolid significant reduction in total lung FDG activity in macaques throughout treatment	Observational NCT04015713	(29)
Antibiotics	Linezolid	Zyvox	Binds prokaryotic 23S rRNA	Community Acquired Pneumonia (CAP)	5-7			NCT02778828	(29)
Statins	Simvastatin	Zocor	HMG-CoA reductase inhibitors to lower cholesterol	Cardiovascular diseases	4.6	2 fold in mouse lungs	1.2 fold reduced lung lesions	Not started	(30)
Statins	Rosuvastatin	Crestor	HMG-CoA reductase inhibitors to lower cholesterol	Cardiovascular diseases	14.2	0.5 log in mouse lungs	1.3 fold reduced lung lesions	Not started	(30)
Statins	Pravastatin	Pravachol	HMG-CoA reductase inhibitors to lower cholesterol	Cardiovascular diseases	2.2	0.9 log in Kramnik mouse lungs RHZE vs RHZE + Pravastatin	3.5 fold in lung involvement RHZE vs RHZE + Pravastatin	Phase 2 NCT03882177	(31)