Table 1.
TB drug discovery pipeline showing the inhibitors targeting lipid biosynthesis
| Pathway targeted | (Proposed) target protein | Inhibitor | ||
|---|---|---|---|---|
| Discovery | Preclinical development | Clinical development | ||
| Mycolic acids | ||||
| InhA | CD117 (Vilchèze et al. 2011) Pyridomycin (Hartkoorn et al. 2012) Triclosan derivatives (Pan and Tonge 2012; North et al. 2013) Novel structural classes (GlaxoSmithKline) |
|||
| HadABC | ISO and TAC analogs (Phetsuksiri et al. 1999; Bhowruth et al. 2006; Alahari et al. 2007; Shahab et al. 2010; Coxon et al. 2013) NAS-21, NAS-91 and analogs (Bhowruth et al. 2008; Gratraud et al. 2008) |
|||
| KasA/KasB | Thiolactomycin and analogs (Pan and Tonge 2012; North et al. 2013) |
|||
| Pks13 | Thiophene compounds; Compound 3′ (Ioerger et al. 2013; Wilson et al. 2013) |
|||
| FadD32 | 4,6-diaryl-5,7-dimethyl coumarins (Stanley et al. 2013) |
|||
| Antigen 85 A, B, and C | Ebselen (Favrot et al. 2013) I3-AG85 (Warrier et al. 2012) |
|||
| MmpL3 | Adamantyl ureas (Grzegorzewicz et al. 2012a) BM212 and analogs (La Rosa et al. 2012; Poce et al. 2013) C215 (Stanley et al. 2012) SPIRO2 and THPP1 (Remuinan et al. 2013) Compound 2 (Ioerger et al. 2013) |
SQ109 (Tahlan et al. 2012) (Sequella) |
||
| Unknown (Inhibition of oxygenated mycolic acid biosynthesis) |
PA-824 (Stover et al. 2000) OPC-67683 (Matsumoto et al. 2006) |
|||
| EthR | ETH “boosters”: BDM 31343 and analogs (Willand et al. 2009; Villemagne et al. 2012) | |||
| Decaprenyl phosphate | ||||
| IspC | Fosfomidomycin analogs (Obiol-Pardo et al. 2011; Uh et al. 2011) |
|||
| Isoprenoid-based biosynthetic precursors | ||||
| PG biosynthesis | MraY | Capuramycin analogs (Sequella) |
SQ641 (lead capuramycin analog) (Sequella) |
|
| PG biosynthesis | WecA | Caprazamycin derivatives (CPZEN-45) (Ishizaki et al. 2013) |
||
| LAM (and AG) biosynthesis |
DprE1 | DNB1 (Christophe et al. 2009) VI-9376 (Magnet et al. 2010) 377790 (Stanley et al. 2012) TCA-1 (Wang et al. 2013) Several synthetic compounds (TB Alliance, Scripps) |
Benzothiazinones (BTZ043) (Makarov et al. 2009) |
|
| Menaquinones | ||||
| MenA | Aurachin RE, Ro 48-8071 and analogs (Dhiman et al. 2009; Debnath et al. 2012) |
|||
| MenB | 1,4-benzoxazines; 4-oxo-4-phenylbut-2-enoates (Li et al. 2010; 2011) |
|||
| MenE | Sulfonyladenosine analogs (Lu et al. 2008; 2012) |
|||
| PGL | ||||
| FadD22 | 5′-O-[N-(4-hydroxybenzoyl)sulfamoyl]-adenosine (Ferreras et al. 2008) |
|||
| Ser/Thr kinases | ||||
| PknA PknB PknG |
Several chemical scaffolds (Vertex Pharmaceuticals Inc.) (Magnet et al. 2010; Danilenko et al. 2011; Lougheed et al. 2011; Chapman et al. 2012) |
|||
See text and the Working Group for New Drugs, Stop TB Partnership (http://www.newtbdrugs.org) for details.