1000/1000
Hot
Most Recent
Tuberculosis (TB), a bacterial infectious disease caused by Mycobacterium tuberculosis (M.tb), causes significant mortality in humans worldwide. The current treatment regimen involves the administration of multiple antibiotics over the course of several months that contributes to patient non-compliance leading to relapse and the development of drug-resistant M.tb (MDR and XDR) strains. Together, these facts highlight the need for the development of shorter TB treatment regimens. Host-directed therapy (HDT) is a new and emerging concept that aims to augment host immune response using drugs/compounds with or without adjunct antibiotics against M.tb infection. Autophagy is a natural catabolic mechanism of the cell that involves delivering the cytosolic constituents to the lysosomes for degradation and recycling the components; thereby maintaining the cellular and energy homeostasis of a cell. However, over the past decade, an improved understanding of the role of autophagy in immunity has led to autophagy activation by using drugs or agents. This autophagy manipulation may represent a promising host-directed therapeutic strategy for human TB.
Class | Drugs/Compounds | Drug Action | Mechanism of Autophagy Activation during Mycobacterial Infection | Model | Reference |
---|---|---|---|---|---|
Small Molecules | |||||
SMER | SMER18 and 28 | - | Induced autophagosome formation | Human PBMCs | [10] |
Analog of AMP | AICAR | Allosteric activation of AMPK kinase which plays a key function in cellular homeostasis | Activates AMPK-PPARGC1A pathway that upregulates CEBPB-dependent autophagy genes and enhances autophagy. | RAW264.7 cells, THP-1 cells (human monocytic cell line), BMDMs, mice and Drosophila | [11] |
Synthetic small molecule | GSK4112 | Activates NR1D1 receptor | Increases autophagic flux via upregulation of TFEB signaling | THP-1 cells, primary human monocyte, murine macrophage cell line, RAW264.7, HEK293T and HepG2 cell lines. | [12] |
GW7647 | Activates PPARα receptor | Increases autophagic flux via upregulation of TFEB signaling, and enhanced lipid catabolism | BMDMs | [13] | |
SRT 1720 | SIRT 1 activator | Enhances autophagy by activating SIRT 1 | THP-1 cells, HMDMs and mice | [14] | |
NSC 18725 | Anti-mycobacterial activity | Modulates autophagy, mechanism unknown | THP-1 cells | [15] | |
Amino acid | Gamma amino Butyric acid | Neurotransmitter inhibitor | Increases autophagic flux via Ca2+-AMPK signaling pathway. Additionally, increases phagosomal maturation | Human PBMCs, HMDMs, RAW264.7 cells and BMDMs | [16] |
Ornithine | Crucial role in disposing of excess nitrogen (ammonia) via the urea cycle | Increases autophagy by reducing ammonia levels thereby upregulating AMPK phosphorylation | Mouse alveolar macrophage, peritoneal macrophages, kupffer cells and BMDMs | [17] | |
Disaccharides | Trehalose | - | Induces autophagic flux by increasing PI(3,5)P2 levels that activate calcineurin triggered translocation of TFEB. Additionally, it causes a pseudo-starvation like a response by inhibiting glucose transporters (GLUT 3 and 8) to induce autophagy | U937, U1.1 and HEK293T cell lines | [18] |
Immunosuppressants | |||||
Macrolide compound | Rapamycin | Forms an immunosuppressive complex by binding to the immunophilin and also a potent mTOR inhibitor | Autophagy induction via mTORC1 complex inhibitor | Raw264.7 cells, HMDMs, Human PBMCs and BMDMs | [6] |
Rapamycin analog | Everolimus * | Inhibits the activation of mTOR by forming a complex with FKBP-12 protein | Autophagy induction via mTORC1 complex inhibitor | - | [19] |
Immunomodulators | |||||
Vitamin | Vitamin D * | Regulation of hormone secretion, cell proliferation, differentiation and immune response | Induces autophagic flux via a signaling cascade that is triggered by the induced expression of human cathelicidin (hCAP-18/LL-37) | Primary human monocytes, HMDMs, THP-1 cells and RAW 264.7 cells | [20][21] |
Cytokine | Interferon-γ (IFN-γ) | Promotes macrophage activation | Activates autophagic flux through vitamin D dependent effector pathway | Human T cells, primary human monocytes and HMDMs | [22] |
Nucleoside analog of imidazoquinoline, a synthetic tricyclic organic molecule | Imiquimod | TLR7 and 8 agonist | Induces Autophagy by increasing mitochondrial ROS that triggers selective autophagy. Additionally, upregulates NO Production via the MEK/ERK1/2 and GSK-3β mediated Pathways. | Raw264.7 cells and THP-1 cells | [23] |
Endotoxin derived from the outer membrane of Gram-negative bacteria | Lipopolysaccharides (LPS) | TLR4 agonist | Activates autophagy and restores M.tb inhibited immune activity | THP-1 cells | [24] |
Plant compounds | |||||
Stilbene | Resveratrol | SIRT 1 activator | Enhances autophagy by activating SIRT 1 | THP-1 cells, HMDMs and mice | [14] |
Flavone glycoside | Baicalin | - | Induces the activation of autophagy by inhibiting PI3K/Akt/mTOR pathway. Additionally, inhibits the PI3K/Akt/NF-kB signal pathway, thereby limiting the NLRP3 inflammasome and subsequent production of pro-inflammatory cytokine IL-1β | Mice, raw264.7 cells, murine macrophage | [25] |
Eurycomanone | Pasakbumin A | - | Induces autophagic flux and TNF-α production via activation of the ERK1/2-signaling pathway and enhances phagosome maturation and lysosome fusion | Raw264.7 cells, and THP-1 cells | [26] |
Polyphenolic compound | Epigallocatechin gallate | - | Induces autophagic flux | Raw264.7 cells and mice | [27] |
Lignans (low molecular weight polyphenols) | Honokiol | SIRT 3 activator | Increases autophagic flux via upregulation of TFEB signaling | Mice, BMDMs, HMDMs and Human PBMCs | [28] |
Legume Lectins | Soybean lectin | - | Induces autophagic flux by activating P2RX7 that triggers Ca2+/AMPK signaling pathway and ROS generation via P2RX7/NF-κB axis | THP-1 cells | [29] |
Antibiotics | |||||
Small molecule–Isonicotinic acid derivative | Isoniazid | Inhibits the enzyme inh A during mycolic acid synthesis | Induces autophagic flux via NOX- derived ROS and calcium, Ca2+ and AMPK dependent pathways | BMDMs and HMDMs | [30] |
Small molecule—Nicotinamide analogue | Pyrazinamide | Disrupts membrane potential, interferes with energy production and inhibits trans-translation by binding to ribosomal protein S1 | Induces autophagic flux via NOX- derived ROS and calcium, Ca2+—dependent AMPK activation | BMDMs and HMDMs | [30] |
Thiopeptide | Thiostrepton | Disrupts prokaryotic translation by inhibiting the dissociation of elongation factor G from ribosomes | ER stress-mediated autophagy activation | Zebrafish and Raw264.7 cells | [31] |
Polyether | Calcimycin | Forms stable complexes with divalent cations and helps in membrane transportation | Induces autophagic flux by activating P2RX7 that triggers Ca2+/AMPK signaling pathway and IL-12 generation via P2RX7/NF-κB axis | THP-1 cells | [32][33] |
Steroids | |||||
Hormones | Dehydroepiandrosterone | Inhibits voltage-gated T-type calcium channels and activates PPARα | Induction of autophagy | THP-1 cells | [34] |
Anticancer drugs | |||||
Signal transduction inhibitor | Gefitinib | EGFR inhibitor | Enhancing host autophagy by inhibiting EGFR-mediated phosphorylation of the downstream signaling molecule p38 MAPK. Depletion of p38 MAPK activates autophagy via p38IP and mATG9 | J774 macrophages and BMDMs | [35] |
Histone deacetylase inhibitor | 4-phenylbutyrate * | Transcription activation via acetylation of histones | LL-37-mediated autophagy activation via P2RX7 receptor which in turn activates AMPK and PI3K downstream of the P2RX7 receptor together with enhanced cytosolic free Ca2+ | HMDMs, and THP-1 cells | [36] |
Kinase inhibitor | Imatinib * | Tyrosine kinase inhibitor | Increases autophagic flux by activating cathepsin D and increasing phagolysosomal acidification via the inhibition of ABL tyrosine kinase | Human PBMCs, HMDMs, human alveolar macrophages | [37] |
Nilotinib | Tyrosine kinase inhibitor | Promotes autophagy by inhibiting the ABL tyrosine kinase-mediated PI3K/Akt/mTOR pathway | THP-1 cells, RAW264.7 cells and BMDMs | [38] | |
Ibrutinib | Bruton’s tyrosine kinase (BTK) inhibitor | Induces autophagy through inhibition of BTK/Akt/mTOR pathway and also facilitates the completion of autophagic flux | THP-1 cells | [39] | |
Estrogen agonists | Bazedoxifene | Selective estrogen receptor modulator | Enhances autophagosome formation via phosphorylation of Akt/mTOR signaling | THP-1 cells | [40] |
Antidiabetic drugs | |||||
Biguanides | Metformin * | Activates AMPK via inhibiting mitochondrial respiratory complex I which elevates 5’-adenosine monophosphate (AMP) levels |
Increases autophagic flux via enhancing autophagosome—lysosome fusion and additionally increases mROS production | THP-1 cells, HMDMs and mice | [41] |
Antidiarrheal drugs | |||||
Synthetic opioid—phenylpiperidine derivative | Loperamide | Decreases peristaltic activity by binding to opiate receptors in the gastrointestinal tract, blocks voltage-dependent calcium channel and calmodulin inhibitor | Increased autophagy induction by upregulating the expression of genes viz., ATG16L1 and LC3 | Mice, HMDMs, murine alveolar cells and Human alveolar macrophages | [42] |
Antiprotozoal agents | |||||
Antiprotozoals | Nitazoxanide | Inhibits pyruvate: ferredoxin oxidoreductase enzyme-dependent electron transport and disrupts metabolism in anaerobic microbes | Autophagy induction via mTORC1 complex inhibitor | THP-1 cells, MCF-7 cells, HEK 293T cells and MEF cells | [43] |
Antiseizure drugs | |||||
First-generation (classic) anticonvulsants | Carbamazepine | Inactivates Na+ channels and inhibits receptors of CNS | Induction of mTOR-independent autophagy through Ins(1,4,5)P3depletion and AMPK activation | RAW264.7 cells, HMDMs, human alveolar macrophages, zebrafish and mice | [44] |
Valproic acid | Inhibits GABA transaminase and increases GABA levels in CNS. It also inhibits histone deacetylase | Induction of mTOR-independent autophagosome formation through ATG12 | RAW264.7 cells, HMDMs and human alveolar macrophages | [44] | |
Lipid-lowering drugs | |||||
Fibrate | Wy14643 | Activates PPARα receptor protein | Increases autophagic flux via upregulation of TFEB signaling, and enhanced lipid catabolism | Mice and BMDMs | [13] |
Statins | Pravastatin *, Rosuvastatin *, Atorvastatin * and Simvastatin | HMG-CoA reductase inhibitors | Promotes autophagy via the AMPK/mTORC1/TFEB axis. Additionally increases phagosome maturation and lysosome fusion |
Human PBMCs, HMDMs, THP-1 cells and mice | [45][46][47][48] |
Mucoactive drug | |||||
Mucokinetics | Ambroxol | Suppresses excessive mucus secretion by inhibiting NO-dependent activation of soluble guanylate cyclase | Induction of autophagy via, the activation of TFEB nuclear translocation | Mice and BMDMs | [49] |
Psychotropic Drugs | |||||
Anti-depressant | Nortriptyline | Norephinephrine and sereotonin reuptake inhibitor | Induces the formation of autophagosomes | HeLa cells and HMDMs | [50] |
Fluoxetine | Sereotonin reuptake inhibitor | Induces autophagy by increasing the secretion of TNF- α | THP-1 cells, RAW264.7 cells, J774 macrophages and BMDMs | [35] | |
Antipsychotics | Prochlorperazine edisylate | D2 dopamine receptor inhibitor | Slows down autophagic flux and progressively increases the acidity of lysozymes | HeLa cells and HMDMs | [50] |