Potential novel therapies for latent tuberculosis infection and IRIS, by class.17,21–23,27,28
| Drug and class | Possible indication | Mechanism of action |
|---|---|---|
| Fluoroquinolones: ofloxacin, moxifloxacin, gatafloxacin | Latent tuberculosis infection | DNA gyrase inhibitor |
| Diarylquinolines: bedaquiline | Latent tuberculosis infection | Mycobacterial ATP synthase inhibitor |
| Nitro-dihydro-imidazo-oxazole: delaminid | Latent tuberculosis infection | Inhibition of mycolic acid synthesis (cell wall) |
| Nitro-imidazo-oxazine: PA-824 | Latent tuberculosis infection | Inhibition of ketomycolate synthesis (cell wall) and production of toxic reactive nitrogen species release following bioreduction |
| Oxalizidinone: sutezolid | Latent tuberculosis infection | Inhibition of protein synthesis in non-replicating bacteria |
| Quinone oxidoreductase: nitazoxanide | Latent tuberculosis infection | Activity against replicating and non-replicating bacilli; induces autophagy |
| Thiazolidinediones: rosiglitazone | Latent tuberculosis infection | Peroxisome proliferator-activated receptor gamma antagonist (lipid-sensing nuclear receptor antagonists); regulation of cytokine production, lipid body biogenesis, and Mycobacterium tuberculosis replication in macrophages |
| Interluekin 1 α/β antagonist: anakinra | IRIS | Reduced pro-inflammatory cytokine production and apoptosis |
| Lipoxygenase-5 inhibitor: zileuton | IRIS | Reduction of pro-inflammatory eicosanoids LTB4 and impaired TNF function |
| TNF inhibitor: adalumimab | IRIS | Granuloma disruption and reactivation of quiescent lesions |
| Potent inhibition of TNF-mediated inflammation | ||
| Secosteroid: cholecalciferol (vitamin D3) | Latent tuberculosis infection, IRIS | Transcription of antimicrobial peptide LL37 (cathlecidin) – induced killing of M tuberculosis and induction of autophagy in infected macrophages |
| Cytochrome P450 blockers: clotrimazole, econazole | Latent tuberculosis infection, IRIS | Reduced calcium-induced potassium efflux from cells leading to activation of NALP3 inflammasome. Proautophagic, anti-inflammatory and anti-apoptotic |
| IL-6 blocker: tocilizumab | IRIS | Blockade of IL-6-mediated inflammation |
| Cyclooxygenase inhibitors: aspirin | IRIS | Reduced synthesis of pro-inflammatory eicosanoids and TNF |
| MMP inhibitor: Ro32-3555, doxycycline | IRIS | Blockade of MMP1, MMP8 and MMP13 (Ro32-3555) or MMP1 and MMP9 (doxycycline) |
| Corticosteroids: dexamethasone, prednisolone, methylprednisolone | IRIS | Blockage of glucocorticoid receptor leading to downregulation of transcriptional regulators NF-B and AP1, resulting in decreased inflammatory cytokines and MMPs |
| COX-2 inhibitor: meloxicam | IRIS | Inhibition of TNF-induced prostaglandin E2 production, and vice versa |
| CCR5 inhibitor: maraviroc | IRIS | Blockage of interaction of CCR5 with endogenous ligands, leading to decreasing influx of CCR5-expressing immune cells to site of inflammation |
Many of these agents are postulated to also have potential to shorten treatment and enhance disease resolution or prevent reactivation. AP1 activator protein 1; CCR5 C-C chemokine receptor type 5; COX-2 cyclooxygenase 2; IL = interleukin; IRIS immune reconstitution inflammatory syndrome; MMP matrix metalloproteinase protein; NF-B nuclear factor kappa-light-chain-enhancer of activated B cells; TNF- tumour necrosis factor .