. 2021 Feb 9;301(1):62–83. doi: 10.1111/imr.12951

Table 1.

HDT compounds and their biological activity against mycobacterial infections

Compound	Biological activity	Model	Pathogen	Reference	Compound	Biological activity	Model	Pathogen	Reference
Phagocytosis and phagosome maturation					Antigen presentation and priming
PRR agonists	↑ PRR‐signaling	In vitro	Mtb	13, 14, 15, 16, 17	MiRNA‐106b inhib.	↑ Antigen presentation	In vitro	Mtb	¹²¹
miRNA‐125 inhib. ^a	↑ TLR2‐signaling	In vitro	Mtb	¹⁹	AGK2	↑ Antigen presentation	Ex vivo, in vivo	Mtb	¹¹⁶
miRNA‐23a‐5p inhib. ^a	↑ TLR2‐signaling	In vitro	Mtb	²⁰	G1‐4A	↑ Th1 immunity (TLR4‐signaling)	In vitro, in vivo	Mtb	¹²²
Imatinib ^a	↑ Phagosomal acidification	In vitro, in vivo, (R)CT	Mtb, Mm	26, 27	LPS + CD40 agonist	↑ Th1 immunity (TLR4‐signaling)	In vitro, in vivo	Mtb	¹³
	↓ Phagocytosis	In vitro, in vivo, (R)CT			Bergenin	↑ Th1 immunity	Ex vivo, in vivo	Mtb	¹²⁴
AZD0530	↑ Phagosomal acidification	In vivo	Mtb	²⁸	D‐1MT ^a	↑ Th1 immunity	Ex vivo, in vivo	Mtb	¹²⁹
AT9283	Unknown	In vitro	Mtb	²⁹	Skewing of T‐cells
ENMD‐2076	Unknown	In vitro	Mtb	²⁹	IFN‐γ	↑ Th1 immunity	In vitro, (R)CT	Mtb, Mav	133, 134, 137, 138, 139, 140
Dovitinib	Unknown	In vitro	Mtb	²⁹	IL‐12	↑ Th1 immunity	In vivo	Mtb	¹⁴¹
Nitazoxanide	↑ Cytoplasmic pathogen recognition	In vitro, (R)CT	Mtb	33, 34	IL‐24	↑ Th1 immunity	In vivo	Mtb	¹⁴²
Metformin ^a	↑ Phagosome maturation	In vitro, in vivo, (R)CT	Mtb	71, 72, 73, 74, 75, 76, 77	FPS‐ZM1	↓ Immune response	In vivo	Mtb	¹⁴⁵
Gefitinib ^a	↑ Lysosomal biogenesis	In vitro, in vivo	Mtb	⁷⁸	Blocking IL‐4	↓ Th2 immunity	In vitro	Mtb	¹³¹
Bedaquilline ^a	↑ (Auto)‐phagolysosome fusion	In vitro, in vivo, (R)CT	Mtb	84, 221, 222, 223	IL‐2	↑ Th1 immunity	In vivo, (R)CT	Mtb, Mav	146, 147, 148, 149
2062 ^a	↑ (Auto)‐phagolysosome fusion	In vitro, in vivo	Mtb	⁸⁵	IL‐2 + HMBPP	↑ Th1 immunity	In vivo	Mtb	¹⁵¹
GM‐CSF ^a	↑ Phagocytosis ↑ (Auto)‐phagolysosome fusion	In vitro, in vivo, CR	Mtb, Mav	86, 87, 88, 89, 90, 91, 92	PBMCs + cytokines	↑ Th1 immunity	CR	Mtb	¹⁵²
		In vitro, in vivo, CR			Prednisolone	↓ Immune response	(R)CT	Mtb	158, 159, 160
Resveratrol ^a	↑ (Auto)‐phagolysosome fusion	In vitro	Mtb	⁷⁰	(Programmed) cell death
SRT1720 ^a	↑ (auto)‐phagolysosome fusion	In vitro, in vivo	Mtb	⁷⁰	Mcl‐1 inhib.	↑ Apoptosis	In vitro	Mtb	¹⁵⁵
Celecoxib ^a	↑ Phagocytosis	In vivo, (R)CT	Mtb	¹⁸⁷	Nicotinamide	↓ Necrosis	In vitro	Mtb	⁹⁹
Statins ^a	↑ Phagosome maturation	In vitro, in vivo, (R)CT	Mtb	181, 184, 185, 186	SQ22536	↑ TNF‐α	In vitro	Mtb	¹⁶¹
Autophagy					H‐89	↑ TNF‐α	In vitro	Mtb	¹⁶¹
Imatinib ^a	↑ Autophagy	In vitro	Mtb	26, 27	Dexamethasone	↓ Necrosis	In vitro, in vivo, R(CT)	Mtb	157, 158, 159, 160, 188, 191
Vitamin‐D	↑ Autophagy	In vitro, (R)CT	Mtb	40, 41, 42, 43, 44, 45, 46, 47, 52		↓ Immune response	In vitro, in vivo, R(CT)
PBA	↑ Autophagy	In vitro, (R)CT	Mtb	49, 50, 51, 52, 53	Doramapimod	↓ Necrosis	In vitro	Mtb	¹⁵⁷
Vitamin‐A (± Zn²⁺)	↑ Autophagy	In vitro, in vivo, (R)CT	Mtb	55, 56, 57, 58, 59, 60, 61, 62	Alisporivir	↓ Necrosis ↓ TNF‐α	In vivo	Mm	¹⁶³
MiRNA‐27a antagomir	↑ Autophagy	In vivo	Mtb	⁶⁶		↓ Necrosis ↓ TNF‐α
Everolimus	↑ Autophagy	In vitro, (R)CT	Mtb	⁶⁸	Desiparamine	↓ Necrosis	In vivo	Mm	¹⁶³
Ibrutinib	↑ Autophagy	In vitro, ex vivo	Mtb	⁶⁹	Cilostazol	↓ TNF‐α	In vivo	Mtb	164, 165
Metformin ^a	↑ Autophagy,	In vitro, in vivo, (R)CT	Mtb	71, 72, 73, 74, 75, 76, 77	Sildenafil	↓ TNF‐α	In vivo	Mtb	164, 165
	↓ Mitochondrial dysfunction	In vitro, in vivo, (R)CT			Ferrostatin 1	↓ Ferroptosis	In vitro, in vivo	Mtb	¹⁷¹
Gefitinib ^a	↑ Autophagy	In vitro, in vivo	Mtb	⁷⁸	D‐1MT ^a	↑ Apoptosis	Ex vivo, in vivo	Mtb	¹²⁹
Bazedoxifene ^a	↑ Autophagy	In vitro	Mtb	⁷⁹	ATP administration ^a	↑ Apoptosis	In vitro	Mtb, Mav	176, 177
Loperamide	↑ Autophagy	In vitro, ex vivo	Mtb	⁸⁰	Cabrohydrate and lipids
Bedaquilline ^a	↑ Autophagy	In vitro, in vivo, (R)CT	Mtb	84, 221, 222, 223	2‐DG	↓ Glycolysis	In vitro	Mtb	¹⁷⁴
2062 ^a	↑ Autophagy	In vitro, in vivo	Mtb		FX11	↓ Glycolysis	In vivo	Mtb	¹⁷⁵
Resveratrol ^a	↑ Autophagy	In vitro	Mtb	⁷⁰	ATP administration ^a	↑ Iron chelation	In vitro	Mtb, Mav	176, 177
SRT1720 ^a	↑ Autophagy	In vitro, in vivo	Mtb	⁷⁰	Clemastine	↑ Immune response?	In vivo	Mm
miRNA‐125 inhib. ^a	↑ Autophagy	In vitro	Mtb	¹⁹	M1	↓ Mitochondrial dysfunction	In vitro	Mtb	¹⁸⁰
miRNA‐23a‐5p inhib. ^a	↑ Autophagy	In vitro	Mtb	²⁰	Ezetimibe	↓ Lipid droplet accumulation	In vitro	Mtb	¹⁷⁹
Statins ^a	↑ Autophagy	In vitro, in vivo, (R)CT	Mtb	181, 184, 185, 186	Statins ^a	↓ Membranal cholesterol incorporation	In vitro, in vivo, (R)CT	Mtb	181, 184, 185, 186
Intracellular killing mechanisms					Eicosanoids
CD157	↑ Reactive oxygen species	In vitro	Mtb	95, 97	PGE2 and/or Zileuton	↑ IL‐1β/prostaglandin signaling	In vivo	Mtb	189, 190
N‐acetyl‐cysteine	↓ Reactive oxygen species	In vitro, in vivo, (R)CT	Mtb	99, 100, 101	Celecoxib ^a	↓ IL‐1β/prostaglandin signaling	In vivo, (R)CT	Mtb	¹⁸⁷
L‐arginine	↑ Reactive nitrogen species	(R)CT	Mtb	107, 108, 109	LTB₄	↑ IL‐1β/prostaglandin signaling	In vivo	Mtb	¹⁸⁷
Bazedoxifene ^a	↑ Reactive oxygen species	In vitro	Mtb	⁷⁹	Ibuprofen	↓ IL‐1β/prostaglandin signaling	In vivo, (R)CT	Mtb	192, 193
Metformin ^a	↑ Reactive oxygen species	In vitro, in vivo, (R)CT	Mtb	71, 72, 73, 74, 75, 76, 77	Aspirin	↓ IL‐1β/prostaglandin signaling	In vivo, (R)CT	Mtb	193, 194, 195, 196, 197, 198
Celecoxib ^a	↑ Reactive oxygen species	In vivo, (R)CT	Mtb	¹⁸⁷	Granuloma: Formation, angiogenesis and hypoxia
Epigenetic regulation					Cipemastat	↓ MMP/ECM degradation	In vivo	Mtb	²⁰⁸
TMP195	↑ Host‐protective epigenetics	In vitro, in vivo	Mtb, Mm	¹¹⁵	MMP‐9 inhib.	↓ MMP/ECM degradation	In vivo	Mm	²⁵
TMP269	↑ Host‐protective epigenetics	In vitro, in vivo	Mtb, Mm	¹¹⁵	Sb‐3ct	↓ MMP/ECM degradation	In vitro, in vivo	Mtb	212, 213
Trichostatin A	↑ Host‐protective epigenetics	In vitro, in vivo	Mtb, Mm	¹¹⁵	AB0046	↓ MMP/ECM degradation	In vivo	Mtb	¹⁶⁶
Resveratrol ^a	↑ Host‐protective epigenetics	In vitro	Mtb	⁷⁰	Doxycycline	↓ MMP/ECM degradation	In vitro, in vivo, (R)CT	Mtb	210, 214
SRT1720 ^a	↑ Host‐protective epigenetics	In vitro, in vivo	Mtb	⁷⁰	Marimastat	↓ MMP/ECM degradation	In vitro, in vivo	Mtb	203, 205
Valproic acid	↑ Host‐protective epigenetics	In vitro	Mtb	¹¹⁷	Batimastat	↓ MMP/ECM degradation	In vivo	Mtb	²⁰⁵
SAHA	↑ Host‐protective epigenetics	In vitro	Mtb	¹¹⁷	MMP‐9 inhib.	↓ MMP/ECM degradation	In vivo	Mtb	²⁰⁵
					Bevacizumab	↓ Angiogenesis	In vivo	Mtb	²¹⁷
					SU5416	↓ Angiogenesis	In vivo	Mm	²¹⁸
					Pazopanib	↓ Angiogenesis	In vivo	Mm	²¹⁸
					AKB‐9785	↓ Angiogenesis	In vivo	Mm	²¹⁹

Abbreviations: (R)CT, (randomized) clinical trial; 2‐DG, 2‐deoxy‐D‐glucose; ATP, adenosine triphosphatases; CR, case report; GM‐CSF, granulocyte‐macrophage colony‐stimulating factor; HMBPP, (E)‐4‐hydroxy‐3‐methyl‐but‐2‐enyl pyrophosphate; IFN‐γ, interferon‐γ; IL, interleukin; inhib., inhibitor; LTB_4, leukotriene‐B4; Mav, Mycobacterium avium; Mm, Mycobacterium marinum; MMP, matrix metalloprotease; Mtb, Mycobacterium tuberculosis; PBA, phenylbutyrate; PBMCs, peripheral blood mononuclear cells; PRR, pathogen recognition receptor; SAHA, suberoylanilide hydroxamic acid; TNF‐α, tumor necrosis factor‐α.

^{^a}

Compounds targeting distinct host intracellular pathways are categorized under multiple sections.

[Correction added on 07 March 2021, after first online publication: the Table 1 has been updated in this version.]