Recent Advances in Antituberculous Drug Development and Novel Drug Targets

Haruaki Tomioka, PhD; Yutaka Tatano, PhD; Ko Yasumoto, PhD; Toshiaki Shimizu, PhD


Expert Rev Resp Med. 2008;2(4):455-471. 

In This Article

Present Status of the Development of New Antimycobacterial Agents

The major goals in the development of new anti-TB drugs are the development of fast-acting drugs that will enable us to reduce the long duration of TB treatment, the development of drugs active against drug-resistant MTB and the development of drugs active against persistent and dormant TB bacilli. New promising anti-tuberculous agents, which are now being subjected to in vitro, in vivo and clinical studies, are indicated in Table 2 . Some of these agents are designed on the basis of novel drug targets and by 3D-QSAR analysis. The following several groups of agents are promising as new anti-TB drugs, and some agents are currently in clinical studies.


A number of nitroimidazoles, especially imidazooxazole and -oxazine derivatives, have been examined for their in vitro and invivo antimicrobial activities against MTB.[62] These agents possess strong antimycobacterial activity, with MICs for MTB of 0.015-1.95 µg/ml.[62] These agents may be promising as anti-TB drugs, although their relatively high levels of carcinogenicity and mutagenicity must be reduced before marketing for clinical use.[62] In this context, it is noteworthy that metronidazole, an antibiotic used to treat anaerobic infections, shows significant activity against static MTB surviving under anaerobic conditions at their MIC,[63] and is also active against MDR-TB strains. A recent study by Iona et al. indicated that metronidazole in combination with RIF was effective in sterilizing long-term nonreplicating (dormant) MTB populations.[64] Metronidazole is currently under Phase II clinical studies as an anti-MDR-TB drug. Of note, at present, the following two agents are the most promising of the anti-TB drugs currently in clinical studies.

Nitroimidazopyran PA-824

Nitroimidazopyran PA-824 (Figure 2A) is highly active against MDR-TB and exhibits bactericidal action against dormant MTB,[65] although its target in MTB has not yet been elucidated (presumably, biosynthesis of mycolic acids and nucleic acids).[62] PA-824 is a prodrug of the nitroimidazole class, requiring activation of an aromatic nitro group to exert an anti-MTB effect.[62] PA-824 is reductively activated in MTB in a manner that depends on the low-redox-potential hydride-transfer coenzyme F420. The activation of PA-824 due to reduction in connection with oxidation of the F420 molecule is catalyzed by an F420-dependent nitroreductase encoded by the Rv3547 gene.[66] The MIC values of PA-824 against polydrug-resistant and MDR-TB strains are 0.03-0.25 µg/ml.[65] Similarly, PA-824 was highly active against a broad panel of MDR-TB isolates (MIC<1µg/ml). PA-824 shows potent microbicidal activity against MTB, mainly due to its inhibitory activity against both protein and lipid synthesis by MTB organisms.[65] Notably, PA-824 exhibits bactericidal activity against both replicating and static MTB in vitro and in MTB-infected mice and guinea pigs.[65] In addition, it has been reported that PA-824 was as active against MTB infection in mice as moxifloxacin (MXFX) in combination with INH and that it prevented the selection of INH-resistant mutants when given to mice in combination with INH.[67] Thus, it appears that PA-824 has the potential to shorten the course of TB chemotherapy by virtue of its activity against nonreplicating MTB organisms. Notably, PA-824 has much reduced mutagenicity compared with the previously reported nitroimidazole compound CGI17341.[62] The Global Alliance for TB Drug Development is now undertaking the development of PA-824 as a promising anti-tuberculous drug candidate. PA-824 has been set to enter a Phase I clinical trial since 2005 in the USA after completion of the required preclinical safety testing.

Figure 2.

New promising anti-tuberculous agents. (A) PA-824, (B) OPC-67683, (C) TMC207, (D) DA-7157 and (E) RBx8700.


Recently, a Japanese company succeeded in remarkably improving the pharmaceutical characteristics of 6-nitro-2,3-dihydroimidazo[2,1-b]oxazoles, structural analogues of a bicyclic nitroimidazole, CGI-17341, by changing the substitutions at the 2-position to a [4-(4-trifluoromethoxyphenoxy)piperidin-1-yl] phenoxymethyl group.[68] Nitroimidazooxazole OPC-67683 (Figure 2B) had very low MIC values (0.006µg/ml) for INH-resistant and RIF-resistant MTB strains, as well as a drug-susceptible MTB strain, H37Rv. OPC-67683, as well as INH, inhibited mycolic acid synthesis. Notably, OPC-67683 inhibited the synthesis of methoxy- and keto-mycolic acids but not the synthesis of a-mycolic acid, while INH inhibited all mycolic acid subclasses. It appears that the drug target of OPC-67683 in MTB is the biosynthesis pathway of mycolic acids. Notably, OPC-67683 requires metabolic activation by MTB, catalyzed by an enzyme encoded for by the Rv3547 gene, before the acquisition of its anti-MTB activity, as in the case of PA-824.[68] It is believed that the Rv3547 protein possesses a reduction potency by virtue of the nitro residue of OPC-67683, and that an intermediate between OPC-67683 and the desnitroimidazooxazole could be the true active form.[68] OPC-67683 displayed an in vivo activity comparable to that of RIF at a dosage of 5 mg/kg. OPC-67683 shows more potent anti-tuberculous activity and lower mutagenicity compared with PA-824. This agent is currently in clinical Phase II studies.

Diarylquinoline TMC207

Diarylquinoline TMC207 (formerly known as R207910) (Figure2C), which targets the proton pump of the ATP synthase of MTB organisms, was recently reported to have a unique spectrum of potent and selective antimycobacterial activity invitro.[69] The oligomeric subunit c (AtpE) of the ATP synthase is the target of TMC207.[70] TMC207 is very potently active against almost all mycobacterial species, including MTB, Mycobacteriumavium complex (MAC), Mycobacterium kansasii and Mycobacterium fortuitum (median MICs ranged from 0.003 to 0.06 µg/ml) and, moreover, Mycobacterium abscessus and Mycobacterium ulcerans (median MICs ranged from 0.25 to 0.5 µg/ml). TMC207 exhibits a good in vitro activity against MTB clinical isolates resistant to the anti-TB drugs INH, RIF, streptomycin (SM), ethambutol (EMB), pyrazinamide (PZA) and MXFX (median MICs ranged from 0.01 to 0.09 µg/ml). However, recent studies revealed natural and acquired resistance to TMC207 in MTB organisms, due to mutations in subunit c of the ATP synthase.[71] In MTB-infected mice, bactericidal activity of TMC207 exceeded those of INH and RIF. In addition, complete culture conversion was achieved after 2months of therapy using some combinations, such as TMC207-PZA, TMC207-INH-PZA, TMC207-RIF-PZA and TMC207-PZA-MXFX.[69,72] Thus, TMC207 is very promising as a chemotherapeutic drug for the treatment of MDR-TB and XDR-TB. TMC207 is currently in Phase IIA clinical trials as a second-line TB drug for MDR-TB. Notably, in Phase I clinical studies, TMC207 was found to be metabolized by cytochrome P450 (CYP)3A4, and the administration of RIF, a potent CYP3A4-inducer, in combination with TMC207 lowers its levels by 50%. In addition, it has been reported that TMC207 exhibited only low levels of early bactericidal activity in TB patients when administered at 400mg/day for 1week. Indeed, the efficacy in reducing the bacterial colony-forming unit (cfu) number in TB patients' sputa was much lower than those of INH (300mg) and RIF (600mg).[73]


Oxazolidinones, including linezolid, eperezolid, PNU-100480, DA-7157 (Figure2D) and RBx8700 (Figure 2E), are active against MTB and exhibit good therapeutic efficacy against MTB infection in mice.[74,75,76,77,78] The oxazolidinones represent a unique family of antimicrobial agents as they have a number of intriguing attributes, as follows:

  • Unique mechanism of action that involves inhibition of ribosomal protein synthesis by interfering with initiation complex formation, resulting in inhibition of protein synthesis at a very early stage and a lack of crossresistance with existing antimicrobial agents;

  • Spectrum of activity that includes a number of important bacterial species;

  • Superior oral and parenteral bioavailability;

  • Low rate of emergence of resistant mutants.

Linezolid and eperezolid exhibit potent antimicrobial activity against both drug-susceptible MTB and MDR-TB isolates (MIC=0.5-2.0 µg/ml) and do not appear to be crossresistant with standard anti-tubercular drugs. Linezolid exhibits excellent activity against clinical MTB isolates and clinical studies are currently underway.[76] Notably, linezolid is bacteriostatic against Gram-positive bacteria, including Staphylococcus aureus, Enterococcus faecalis and Enterococcus faecium, differing from daptomycin, which exhibits bactericidal activity against these bacteria.[79] Linezolid is also bacteriostatic against MTB, while a new oxazolidinone, RBx8700 (see later), exhibits strong bactericidal action.[75,80]

In a murine TB model, these new oxazolidinones displayed chemotherapeutic efficacy in the order: PNU-100480 > linezolid > eperezolid.[74] Linezolid in combination with other drugs, such as EMB, SM, PZA and amikacin, exhibited good therapeutic efficacy in clinical treatment of drug-resistant TB patients, while peripheral neuropathy and bone marrow depression were occasionally observed in some patients.[81] Notably, TB patients receiving linezolid showed sterilized respiratory samples early after initiating therapy, thereby indicating the favorable bactericidal activity of linezolid in the clinical treatment of TB patients.[81] While linezolid has been approved for clinical use in MRSA infection and is currently under investigation in Phase II clinical studies as an anti-tuberculous drug, PNU-100480 has not been developed further, presumably because of potential cost.

Newly synthesized oxazolidinone DA-7867 was found to be 16-times more active against 67 clinical isolates of MTB compared with linezolid.[76,82] However, this agent has poor solubility in water. A highly water-soluble analogue DA-7157 is active against both drug-susceptible MTB and MDR-TB clinical isolates (MIC50=0.25 µg/ml).[77] Another newly synthesized oxazolidinone, RBx8700, exhibits excellent activity against drug-susceptible MTB (MIC50=0.032 µg/ml) and good activity against MDR-TB (MIC50=0.25 µg/ml).[76] RBx8700 had a 16-times lower MIC50 for MDR-TB isolates than linezolid (0.25 vs 4 µg/ml)[80] and exhibited in vivo activity against MTB infection in mice, which was superior to PNU-100480 and EMB.[83] Further studies on the in vivo activities, pharmacokinetics and adverse effects of DA-7157 and RBx8700 will be carried out toward their clinical application.

Ethylene Diamine SQ-109

SQ-109, N-geranyl-N-(2-adamantyl)ethane-1,2-diamine, exhibits potent antimicrobial activity against drug-susceptible and -resistant MTB, with MICs ranging from 0.16 to 0.64mg/ml, and interacts synergistically with INH and RIF in inhibiting MTB, including RIF-resistant strains.[84] SQ-109 inhibits cell wall synthesis in a select group of microorganisms. In a mouse model of chronic TB, the substitution of SQ-109 for EMB improved the efficacy of combination drug therapy with first-line TB drugs RIF and INH, with or without PZA.[85] This drug is currently undergoing Phase Ib clinical studies.

Pyrrole Derivatives

The antimycobacterial activity of pyrrole compounds was first reported by Deidda et al.[86] The most active pyrrole, BM212, 1,5-diaryl-2-methyl-3-(4-methylpiperazine-1-yl)methyl-pyrrole, exhibited good in vitro activity against MTB, including drug-resistant MTB (MIC=0.7-1.5 µg/ml). BM212 was also strongly inhibitory against MAC. Pyrrole LL3858 was synthesized as a series of pyrrole compounds.[87] LL3858 exhibits good in vitro and in vivo activiites against both drug-sensitive and -resistant MTB.[87] In murine experimental TB models, complete killing of MTB has been observed to occur as early as 19 days, when combined with INH, RIF and PZA.[88] LL3858 is currently in Phase I clinical studies.


The development of fluoroquinolones as anti-TB drugs is important. Levofloxacin and ciprofloxacin in combination with other anti-TB drugs are generally used in the USA and some other countries for the treatment of MDR-TB. There is crossresistance or antagonism with other classes of antimycobacterial drugs. Fluoroquinolones show good bioavailability and favorable pharmacokinetics.[89] Moreover, the incidence and severity of adverse effects are generally low for fluoroquinolones.[89] Thus, they may be used in the long-term therapy of TB patients as first-line drugs in combination with other antimycobacterial agents,[90] although there are still somewhat insufficient clinical data for their use as a first-line treatment of TB. An 8-methoxy quinolone, MXFX, is currently being codeveloped as a promising anti-TB drug. MXFX exhibits the most potent in vitro and in vivo anti-MTB activity among existing or developing fluoroquinolones, as in the case of another 8-methoxy quinolone, gatifloxacin, as follows: MIC50=0.12-0.5µg/ml; MPC50=0.6µg/ml; potent combined in vitro activity in combination with INH or RIF and appreciable levels of bactericidal activity against dormant MTB organisms.[91,92,93] These 8-methoxy quinolones are efficacious in exerting potent anti-TB therapeutic activities in humans and animals, particularly when added to multidrug regimens,[90,94] suggesting their usefulness as first-line drugs for TB, especially for the treatment of proven MDR-TB, for the empirical treatment of TB in settings of high rates of MDR-TB and for patients with severe adverse reactions to ordinary first-line drugs.[90] MXFX is currently undergoing Phase II clinical trials and rifaquin (rifapentine plus MXFX) is in Phase III studies. In addition, levofloxacin and gatifloxacin are now in Phase II and III clinical studies, respectively.


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