Table 1.

Main anti-tuberculosis drug candidates in clinical development reported in the review, their mechanism of action, molecular targets, and mode of resistance.

Compound	Class	Identification strategy	Mode(s) of action	Target(s)	Mechanism of resistance	References
Bedaquiline	Diarylquinoline	Whole-cell screening of prototypes of different chemical series	(i) Inhibition of ATP biosynthesis (ii) Efflux inhibition	Subunit c of the ATPase	(i) Mutations in the subunit c of the ATPase (ii) Mutations in the transcriptional repressor Rv0678 (MmpR5) (iii) Substrate of efflux pumps—MmpS5-MmpL5 system	(Andries et al., 2005) (Andries et al., 2014) (Hartkoorn et al., 2014)
TBAJ-587	Diarylquinoline	Optimization of diarylquinolines	Inhibition of ATP biosynthesis	Subunit c of the ATPase	(i) Mutations in the subunit c of the ATPase (ii) Mutations in the transcriptional repressor Rv0678 (MmpR5) (iii) Substrate of efflux pumps—MmpS5-MmpL5 system	(Tong et al., 2017) (Choi et al., 2017) (Sutherland et al., 2018)
PA-824	Nitroimidazole	Whole-cell screening of a series of 3-substituted nitroimidazopyrans	(i) Pro-drug (ii) Inhibition of ATP biosynthesis (iii) Respiratory poison by nitric oxide (NO) production	Deazaflavin (cofactor F(420 dependent nitroreductase (Ddn)	(i) Mutations in the activator ddn (ii) Mutations in the genes fgd1, fbiA, fbiB, and fbiC encoding the 6-phosphate dehydrogenase Fgd1 required for cofactor F420 biosynthesis	(Stover et al., 2000); (Manjunatha et al., 2006); (Manjunatha et al., 2009), (Singh et al., 2008) (Choi et al., 2001) (Choi et al., 2002)
OPC-67683	Nitroimidazole	Whole-cell screening for inhibitors of mycolic acid biosynthesis	(i) Pro-drug (ii) Inhibition of ATP biosynthesis (iii) Respiratory poison by NO production	Deazaflavin (cofactor F(420)) dependent nitroreductase (Ddn)	(i) Mutations in the activator ddn (ii) Mutations in the genes fgd1, fbiA, fbiB, and fbiC encoding the 6-phosphate dehydrogenase Fgd1 required for cofactor F420 biosynthesis	(Matsumoto et al., 2006) (Stover et al., 2000); (Singh et al., 2008) (Choi et al., 2001) (Choi et al., 2002)
Q-203	Imidazopyridine amide	Phenotypic screening of various commercial chemical libraries in infected macrophages	Inhibition of the cytochrome bc1 complex (complex III)	Cytochrome b subunit (QcrB) of the cytochrome bc1 complex	(i) Mutations in the qcrB gene (ii) Substrate of efflux pumps	(Pethe et al., 2013) (Jang et al., 2017)
SQ-109	1,2-ethylene diamine	Whole-cell screening of ethambutol derivatives	(i) Inhibits mycolic acid biosynthesis (ii) Inhibition of menaquinone synthesis	(i) Mycobacterial trehalose monomycolate transporter MmpL3 (ii) MenA and MenG	(i) Mutations in the mmpL3 gene (ii) Mutations in menA and menG genes	(Protopopova et al., 2005) (Sacksteder et al., 2012) (Li K. et al., 2014) (Li W. et al., 2014)
BTZ-043	Benzothiazinone	Whole-cell screening of a series of sulfur-containing heterocycles	(i) Pro-drug (ii) Inhibit arabinan biosynthesis	Decaprenylphosphoryl-β-d-ribose 2′-epimerase (DprE1)	Mutations in the activator encoding the gene dprE1	(Makarov et al., 2009) (Trefzer et al., 2010)
PBTZ-169	Benzothiazinone	Whole-cell screening of a new generation of BTZ derivatives from BTZ043	Inhibit arabinan biosynthesis	Decaprenylphosphoryl-β-d-ribose 2′-epimerase (DprE1)	Mutations in the activator encoding gene dprE1	(Makarov et al., 2014)
AU-1235	Adamantyl urea	Whole-cell screening of a diverse commercial compound libraries	Inhibits mycolic acid transport	Mycobacterial trehalose monomycolate transporter MmpL3	Mutations in the mmpL3 gene	(Grzegorzewicz et al., 2012)
TB-47	Pyrazolopyrimidine	Phenotypic screening	–	–	–	(Tang et al., 2015) (Zhang et al., 2017)