. 2015 Sep 16;61(Suppl 3):S200–S216. doi: 10.1093/cid/civ621

Table 1.

Candidate Tuberculosis Host-Directed Therapeutic Agents

Drug Class/Target	Drug Examples	Probable Therapeutic Mechanism
MAPK cascade inhibitors [4] RAF-B MEK ERK JNK	Vemurafenib^a, dabrafenib Trametinib^a [6] SCH772984 CC-930 [7], sitagliptin^a	Varies: anti-inflammatory^b/metabolic dysfunction – OR – interfering with tuberculosis pathogenic effect on signaling
Small GTPase inhibitors [8] Ras (RAF-MEK-ERK) Rho/ROCK [9]	Tipifarnib [10], salirasib [11], fasudil^c [12], statins^a [13], metformin^a [14]	Same
Wnt inhibitors [15]	OMP-54F28 [16], tankyrase inhibitors [17], clofazimine^a [18]	Same, but more complex
Protein kinase inhibitors Tyrosine kinase inhibitors [19, 20] c-abl, c-kit JAK/STAT VEGF EGFR Ser-thr kinase inhibitors SIK inhibitors	Imatinib^a [21, 22] and others Tofactinib^a [23], ruxolitinib^a Pazopanib^a [24] Gefitinib^a [25] Dasatinib^a, bosutinib^a [26] (approved as TKIs)	Increase autophagy and myeloid cell mobilization Anti-inflammatory Normalize vasculature in granulomas to improve drug penetration Increase autophagy, anti-inflammatory Anti-inflammatory and decrease M2 polarization
AMPK activators [27]	Metformin^a [28], AICAR [29], AZD-769662 Berberine^a [30], resveratrol^a [31], acetylsalicylic acid^a	Anti-inflammatory, increase autophagy, and improve DC, TH1 CD4 cell, and CD8 memory cell development
AMPA channel receptor blockers	Topiramate^a [32], perampanel^a [33]	Anti-inflammatory
PARP inhibitors [34, 35]	NAD intermediates (NAM^a, NR^a, NMN^a), tetracyclines^a, olaparib^a, many in development	Anti-inflammatory, increase autophagy, improve effector T-cell function, and inhibit Tregs
Sirtuins Activators [36] Inhibitors [37]	Resveratrol^a [31], NAD intermediates, statins^a [38], metformin^a, berberine^a [30], and many STACs in development Sirtinol, cambinol, tenovin, others	Anti-inflammatory and increase autophagy Increase Th1/Treg ratio
PI3K-AKT-mTOR pathway inhibitors [39,40] Direct mTOR inhibitors [41, 42]	Idelalisib^a, afuresertib [43], perifosine [44], MK-2206 [45], GSK-609693, [46], triciribine [47] Sirolimus^a, everolimus^a, ridaforolimus	Increase autophagy, decrease M2 polarization, and improve DC, Th1 CD4 cell, and CD8 memory cell development Same
PTEN activator	Resveratrol^a [48]	Increase autophagy and decrease M2 polarization
p53 activator	Nutlin 3A [49]	Increase autophagy and decrease M2 polarization
Autophagy inducers [50]	Imatinib^a/other TKIs, metformin^a, statins^a, verapamil^a, selective serotonin reuptake inhibitors^a, carbamazepine^a, sirolimus^a	Increase autophagy: improve pathogen killing, clearance of proinflammatory organism components, and processing of antigenic material for T-cell presentation
Oxidative stress reduction agents [51]	Silymarin^a [52], Tanshinone [53]	Anti-inflammatory and improve macrophage functions, including autophagy
ERS/UPR reduction agents Inflammasome inhibitors [54]	Phenylbutyrate^a [55], ursolic acid^a [56] Fasudil^c [57], tauroursodeoxycholic acid^a [58] β-hydroxybutyrate^a [59], MCC950 [60], sitagliptin^a	Anti-inflammatory and improve macrophage functions, including autophagy
LOX-1 and other scavenger receptor suppressors Angiotensin II receptor inhibitors [61]	Ellagic acid^a [62], coenzyme Q10^a [63] Docosahexaenoic acid^a [64], sitagliptin^a, statins^a [65], Tanshinone derivatives [66] Telmisartan^a [67], others	Decrease M2 polarization/foam cell development, improve macrophage functions
Cathelicidin inducers [68]	Vitamin D^a, phenylbuturate^a, nicotinamide^a, resveratrol^a, pterostilbene^a	Induction of antimicrobial peptides, improve lipid metabolism, and decrease M2 polarization
Dipeptide dipeptiase-4 inhibitors	Sitagliptin^a [69], others	Anti-inflammatory/decrease inflammasomes, improve lipid metabolism and macrophage function, decrease M2 polarization, and preserve CXCL10 on effector T cells
Mevalonate metabolism inhibitors	Amino-bisphophonates^a, eg, zolandronate [70]	Enhance γδ T-cell activity and bridging between and innate and adaptive immunity
Highly pleiotropic agents	Metformin^a, statins^a, phenylbutyrate, Fasudil^c, berberine^a, sitagliptin^a
Combinations	Fasudil^c and statins^a (ROCK inhibition) [71] Vitamin D^a and phenylbutyrate^a [72] (cathelicidin induction) Tipifarnib and statins^a [73] (RAS-ERK pathway inhibition)

Bold text indicates that agent has been evaluated for potential tuberculosis host-directed therapeutic activity in a published study.

Abbreviations: AICAR, 5-Aminoimidazole-4-carboxamide ribonucleotide; AKT, serine/threonine protein kinase; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; AMPK, adenosine monophosphate-activated protein kinase; DC, dendritic cell; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; ERS, endoplasmic reticulum stress; JAK, Janus tyrosine kinase; JNK, c-Jun N-terminal kinase; LOX-1, lectin-like oxidized low-density lipoprotein receptor 1; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase; mTOR, mechanistic target of rapamycin; NAM, nicotinamide; NMN, nicotinamide mononucleotide; NR, nicotinamide riboside; PARP, poly(ADP-ribose) polymerase; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatidylinositol-3, 4, 5,-trisphosphate 3-phosphatase; RAF, rapidly accelerated fibrosarcoma; RAS, Rat sarcoma protein; ROCK, Rho-associated coiled-coil containing kinase; SIK, salt-inducible kinase; STACs, sirtuin activating compounds; STAT, signal transducers and activators of transcription; TKI, tyrosine kinase inhibitor; UPR, unfolded protein response; VEGF, vascular endothelial growth factor.

^a US Food and Drug Administration approved or available over the counter.

^b Decreasing inflammatory reaction may allow improved drug and immune cell access to lesions; decrease tissue damage; possibly allow “wake and whack” strategies to improve antimicrobial response by allowing activation of nonreplicating bacilli with low metabolism levels.

^c Approved in other countries with stringent regulatory authorities.