Advances in Key Drug Target Identification and New Drug Development for Tuberculosis

Table 1

Summary of targets of anti-TB drugs.

Action targets		Gene Bank	Human homologue	New drugs/lead compounds	Structure	Mechanism of action	NCT number	Phase	Notes	References
Cell wall biosynthesis	InhA	rv1484	None	Diaryl ether compounds	—	—	—	—	Undesirable bioavailability, limited solubility, and certain cytotoxicity	[6, 8, 9, 11, 12, 168]
	FabH	rv0533c	None	Alkaloids and small molecule compounds	—	—	—	—	In vitro experiments	[15–17]
	Methoxy-keto-mycolic acid	—	None	Delamanid		Inhibit the mycolic acid biosynthesis of Mtb cell wall	NCT03828201	II	Not yet recruiting	[18–24, 169]
							NCT03959566	II	Recruiting
							NCT04550832	II	Recruiting
							NCT05007821	II	Recruiting
							NCT04518228	IV	Recruiting
				Pretomanid (PA-824)			NCT04179500	II	Recruiting
							NCT05040126	III	Recruiting
							NCT04207112	II, III	Recruiting
				TBA-354			NCT02606214	I	Terminated (mild reversible neurotoxicity)
	DprE1	rv3790	None	BTZ-043		Inhibit the arabinogalactan biosynthesis of Mtb cell wall	NCT04874948	I	Completed	[4, 25–29, 170]
							NCT04044001	I, II	Recruiting
				PBTZ-169			NCT03334734	II	Terminated (very slow enrollment)
							NCT03776500	I	Completed
				OPC-167832			NCT03678688	I, II	Recruiting
				TBA-7371			NCT03199339	I	Completed
							NCT04176250	II	Recruiting
	WecA	rv1302	None	CPZEN-45			—	Preclinical study	Poor solubility and potentially low bioavailability	[30]
	RmlC	rv3465	None	Benzimidazolone derivatives			—	—	Mild antitubercular activity	[31, 32]
	MurX	rv2156c	None	SQ641		Inhibit the peptidoglycan biosynthesis of Mtb cell wall	—	Preclinical study	Low solubility and low bioavailability	[33–35]
	MbtI	rv2386c	None	Natural products and small molecule compounds	—		—	—	Carbonyl and 7-hydroxyl groups are the necessary structures of inhibitors	[36–38, 40, 171]
	MbtA	rv2384		Nucleic acid analogues					Short half-life and low bioavailability
	Alr and DdlA	rv3423c; rv2981c	None	—	—		—	—	Research needs to be further	[41, 42]
	GlmU	rv1018c	None	Natural products and small molecule compounds	—		—	—	In vitro experiments	[43–46, 172]
	Ino1	rv0046c	Yes	—	—	—	—	—	Inhibitors rarely reported so far	[48, 49, 100]
	MEP pathway	—	None	Alkaloids and small molecule compounds	—	—	—	—	Research needs to be further	[50, 51]
Protein biosynthesis and breakdown	50s ribosomal subunit	—	None	AZD-5847		Inhibit the proteins biosynthesis of Mtb	NCT01516203	II	Completed	[54, 55]
	23s rRNA	—	None	Sutezolid			NCT03959566	II	Recruiting	[57–63]
							NCT03237182	IV	Recruiting
				Delpazolid			NCT04550832	II	Recruiting
							NCT04939779	I	Completed
				Contezolid			NCT03747497	II	Completed
	LeuRS	—	Yes	GSK-3036656			NCT03557281	II	Completed	[64]
	ClpP1; ClpP2	rv2461c; rv2460c	Yes	Acyldepsipeptide antibiotics (ADEPs) and cyclomarinA	—	—	—	—	Research needs to be further	[69]
DNA related enzymes	GyrA; rv0006		None	DC-159a		Inhibit the activity of DNA gyrase, blocks DNA replication and transcription to lead Mtb death	—	Preclinical study	Mtb is more resistant to DC-159a	[77]
	GyrB; rv0005		None	SPR720				I	Completed	[78]
	topA	rv3646c	Yes	Boldine-derived alkaloids		—	—	Screening and structural optimization	Inhibition activity at μM level	[82–84]
Energy metabolism	ATP synthase	—	Yes	Bedaquiline		Inhibit the ATP synthase of Mtb to block the energy supply	NCT04630145	II and III	Recruiting	[85, 86]
							NCT04207112	II and III	Recruiting
	NADH-2	rv1854c	None	Phenothiazines, quinoline pyrimidines, quinazolones, and DPI analogues	—	—	—	—	More serious side effects	[90–94, 173]
	Respiratory cytochrome bc1 complex	—	Yes	Q203		Inhibit the synthesis of ATP by acting on the respiratory cytochrome bc1 complex	NCT03563599	II	Completed	https://www.clinicaltrials.gov/ct2/show/NCT03563599?cond = Q203&draw =2&rank =1
	MenB	rv0548c	None	Succinyl benzoate derivatives and benzoxazine derivatives	—	—	—	—	In vitro experiments	[96–98]
Lipid metabolism	Fatty acid desaturase (DesA3)	rv3229c	Yes	Thiocarlide		Inhibit desA3 to decrease oleic acid and stearic acid synthesis of Mtb	—	—	Require structure optimization	[99, 101, 174]; [100]
	Pantothenate synthetase (PanC)	rv3602c	None	Small molecule compounds	—	—	—	—	In vitro experiments	[102]
Signal transduction pathway	Shikimate pathway	rv2539c	None	Natural products and small molecule compounds	—	—	—	—	In vitro experiments	[103, 104, 175]
Other targets	FtsZ	rv2150c	None	Natural products and small molecule compounds	—	—	—	—	In vitro experiments	[106–109, 111]
	MmpL	rv0206c	None	BM212		Inhibit membrane proteins mmpL of Mtb	—	Preclinical study	Poor pharmacokinetics and more severe toxic reactions	[112–118, 176]
				SQ109			NCT01785186	II	Completed
	STPK	—	Yes	—	—	—	—	—	Antituberculosis activity of inhibitors is not significant	[119–122]
	AhpD	rv2429	None	—	—	—	—	—	Inhibitors rarely reported so far	[123]
	NATs	rv3566c	Yes	—	—	—	—	—	Inhibitors rarely reported so far	[124]
	Diterpene cyclase	rv3377c	None	Diterpenoid and triterpenoid acids	—	—	—	—	Research needs to be further	[125–128]
	Tuberculosinol phosphatase	rv3378c
	ICL	rv0467	None	Natural products and synthetic compounds	—	—	—	—	In laboratory research	[129–131]
	Redox-related enzymes (cytochrome P450 enzymes)	—	Yes	Azole antifungals	—	—	—	—	Prevent the synthesis of ergosterol from fungal cell membrane	[132]
	MshA	rv0486	None	Adenosine derivatives and synthetic compounds	—	—	—	—	Research needs to be further	[133–136]
	MshC	rv2130c				—
	PptT	rv2794c	None	8918		Inhibit PptT to block the activation of Pks13 enzyme and various type-І Pks	—	—	Short half-life	[137, 138]
	MptpA	rv2234	None	Natural products and synthetic compounds	—	—	—	—	The best inhibition activity at nM level	[139–142, 177]
	MptpB	rv0153c
	Biofilm	—	None	C10		Prevent the formation of biofilm to make Mtb more susceptible to antibiotics	—	—	Research needs to be further	[145]