TABLE 2.
Targets, drug candidates, and actions of host‐directed therapeutics for tuberculosis.
| Effect of HDT | Target | Typical compound | Mechanism of action | Drug stage for TB | |
|---|---|---|---|---|---|
| Enhancing host immune defense | Myeloid‐derived suppressor cells (MDSCs) | Tasquinimod 341 | Antagonizing MDSCs to activate T cells | Biological test | |
| Tyrosine kinase (TK) | Imatinib 348 | Inhibition of TK to activate phagolysosomal acidification | Phase II | ||
| Ca2+‐adenosine monophosphate‐activated protein kinase (AMPK) | GABA 349 | Inhibition of Ca2+‐AMPK to enhance phagosomal maturation | Biological test | ||
| Indoleamine 2,3‐dioxygenase (IDO) | D‐1MT 355 | Inhibition of IDO to increase CD4 T cells | Biological test | ||
| Heme oxygenase‐1 (HO‐1) | SnPPIX 356 | Inhibition of HO‐1 to increase iNOS and NO production | Biological test | ||
| Histone deacetylases (HDACs) | Trichostatin A 362 | Inhibition of HDAC6 to modify epigenetics | Biological test | ||
| Interfering with the use of host mechanism | Regulation of autophagy | Mammalian target of rapamycin (mTOR)/AMPK | Rapamycin 375 | Regulation of mTOR/AMPK to enhance autophagy | Biological test |
| Extracellular regulated protein kinase ERK1/2 | Pasakbumin A 393 | Activating ERK1/2 to enhance autophagy | Biological test | ||
| Epidermal growth factor receptor (EGFR) | Gefitinib 399 | Inhibition of STAT3 to enhance autophagy | Biological test | ||
| Tyrosine kinase (TK) | Ibrutinib 401 | Inhibition of BTK/Akt/mTOR to enhance autophagy | Biological test | ||
| Transcription factor EB (TFEB) | Statins 403 , 404 , 405 | Activating AMPK/mTORC1/TFEB to enhance autophagy | Biological test | ||
| Sirtuin 1/3 (SIRT1/3) | Resveratrol 406 | Activation of SIRT1/3 to enhance autophagy | Biological test | ||
| Toll‐like receptor 7 (TLR7) | Imiquimod 409 | Agonism of TLR7 to enhance autophagy | Biological test | ||
| Intervention of granuloma formation | Vascular endothelial growth factor (VEGF) | Pazopanib 415 | Inhibition of VEGF to impede granuloma angiogenesis | Biological test | |
| Angiopoietin‐2 (ANG‐2) | AKB‐9778 418 | Inhibition of ANG‐2/TIE2/VE‐PTP to reduce infection‐induced vascular permeability | Biological test | ||
| Regulation of cell death | Myeloid cell leukemia sequence‐1 (Mcl‐1) | Sabutoclax 443 | Inhibition of Mcl‐1 to activate apoptosis | Biological test | |
| Complex I | Metformin 396 | Inhibition of complex I to reduce necrosis | Phase II | ||
| Ferroptosis | Ferrostatin‐1 446 | Inhibition of ferroptosis to reduce necrosis | Biological test | ||
| Mitogen‐activated protein kinase (MAPK) | Corticosteroids 447 | Inhibition of p38 MAPK to reduce necrosis | Phase II | ||
| Domain‐like receptor protein 3 (NLRP3) | Baicalin 453 | Inhibition of PERK/TXNIP/NLRP3 to reduce pyroptosis | Biological test | ||
| Limiting immunopathology | Matrix metalloproteinase (MMP) | Doxycycline 466 | Inhibition of MMP to reduce cavitary pathology | Phase III | |
| 5‐Lipoxygenase (5‐LOX) | Zileuton 477 | Inhibition of 5‐LOX to regulate lipid metabolism | Biological test | ||
| Cyclooxygenase‐2 (COX‐2) | NSAIDs 481 | Inhibition of COX‐2 to reduce inflammatory response | Phase II | ||
| Glucocorticoid receptor (GR) | Corticosteroids 484 | Binding to GR to reduce inflammatory response | Phase II | ||
| Poly(ADP‐ribose) polymerase 1 (PARP1), | PJ‐34 487 | Inhibition of PARP1 to reduce inflammatory response | Biological test | ||
| Phosphodiesterase‐4 (PDE‐4) | Dovramilast 488 | Inhibition of PDE‐4 to reduce inflammatory response | Phase II | ||