Shortening Treatment by Advancing Novel Drugs

Inclusion Criteria: 1. Signed written consent or witnessed oral consent in the case of illiteracy, prior to undertaking any trial-related procedures. 2. Male or female, aged 18 years or over. 3. Body weight (in light clothing and no shoes) ≥ 30 kg. 4. Sputum positive for tubercule bacilli (at least 1+ on the International Union Against Tuberculosis and Lung Disease (IUATLD) and World Health Organization (WHO) scale on smear microscopy at the trial laboratory. 5. Drug-Sensitive TB treatment arms subjects should be: * sensitive to rifampicin by rapid sputum based test (may be sensitive or resistant to isoniazid) AND * either newly diagnosed for TB or have a patient history of being untreated for at least 3 years after cure from a previous episode of TB. If they are entered into the trial due to being sensitive to rifampicin by rapid sputum based test, however on receipt of the rifampicin resistance testing using an indirect susceptibility test in liquid culture this shows they are rifampicin resistant, they will be: * Excluded as late exclusions; * Possibly replaced as determined by the sponsor. 6. MDR-TB treatment arm subjects should be resistant to rifampicin by rapid sputum based test (may be sensitive or resistant to isoniazid). 7. A chest x-ray which in the opinion of the investigator is compatible with pulmonary TB. 8. Be of non-childbearing potential or using effective methods of birth control, as defined below: Non-childbearing potential: * Subject - not heterosexually active or practice sexual abstinence; or * Female subject or male subjects female sexual partner - bilateral oophorectomy, bilateral tubal ligation and/or hysterectomy or has been postmenopausal with a history of no menses for at least 12 consecutive months; or * Male subject or female subjects male sexual partner - vasectomised or has had a bilateral orchidectomy minimally three months prior to screening; Effective birth control methods: * Double barrier method which can include a male condom, diaphragm, cervical cap, or female condom; or * Female subject: Barrier method combined with hormone-based contraceptives or an intra-uterine device for the female patient. * Male subjects' female sexual partner: Double barrier method or hormone-based contraceptives or an intra-uterine device for the female partner. and are willing to continue practising birth control methods and are not planning to conceive throughout treatment and for 12 weeks (male subjects) or 1 week (female subjects) after the last dose of trial medication or discontinuation from trial medication in case of premature discontinuation. (Note: Hormone-based contraception alone may not be reliable when taking IMP; therefore, Exclusion Criteria: 1. Any non TB related condition (including myasthenia gravis) where participation in the trial, as judged by the investigator, could compromise the well-being of the subject or prevent, limit or confound protocol specified assessments. 2. Being or about to be treated for Malaria. 3. Is critically ill and, in the judgment of the investigator, has a diagnosis likely to result in death during the trial or the follow-up period. 4. TB meningitis or other forms of extrapulmonary tuberculosis with high risk of a poor outcome, or likely to require a longer course of therapy (such as TB of the bone or joint), as judged by the investigator. 5. History of allergy or hypersensitivity to any of the trial IMP or related substances, including known allergy to any fluoroquinolone antibiotic, history of tendinopathy associated with quinolones or suspected hypersensitivity to any rifampicin antibiotics. 6. For HIV infected subjects any of the following: * CD4+ count \<100 cells/µL; * Karnofsky score \<60%; * Received intravenous antifungal medication within the last 90 days; * WHO Clinical Stage 4 HIV disease. 7. Resistant to fluoroquinolones (rapid, sputum - based molecular screening tests). If they are entered into the trial due to being sensitive to fluoroquinolones by rapid sputum based test, however on receipt of the fluoroquinolones resistance testing using an indirect susceptibility test in liquid culture this shows they are fluoroquinolones resistant, they will be: * Excluded as late exclusions; * Possibly replaced as determined by the sponsor. 8. Resistant to pyrazinamide (rapid, sputum - based molecular screening tests). Drug-Sensitive TB treatment arms subjects may be entered prior to receipt of the rapid, sputum - based molecular pyrazinamide resistance screening test result. On receipt of the result, if they are resistant, they will be: * Excluded as late exclusions; * Possibly replaced as determined by the sponsor. MDR-TB treatment arm subjects may not be entered prior to receipt of the rapid, sputum - based molecular pyrazinamide resistance screening test result showing they are sensitive to pyrazinamide. 9. Having participated in other clinical trials with investigational agents within 8 weeks prior to trial start or currently enrolled in an investigational trial. 10. Subjects with any of the following at screening (per measurements and reading done by Central Electrocardiogram (ECG) where applicable): * Cardiac arrhythmia requiring medication; * Prolongation of QT/QTc interval with QTcF (Fridericia correction) \>450 ms; * History of additional risk factors for Torsade de Pointes, (e.g., heart failure, hypokalemia, family history of Long QT Syndrome); * Any clinically significant ECG abnormality, in the opinion of the investigator. 11. Unstable Diabetes Mellitus which required hospitalization for hyper- or hypo-glycaemia within the past year prior to start of screening. Specific Treatments 12. Previous treatment with PA-824 as part of a clinical trial. 13. For DS-TB treatment arms: Previous treatment for tuberculosis within 3 years prior to Day (-9 to -1)(Screening). Subjects who have previously received isoniazid prophylactically may be included in the trial as long as that treatment is/was discontinued at least 7 days prior to randomization into this trial. For the MDR-TB Subjects: Previous treatment for MDR-TB, although may have been on a MDR TB treatment regimen for no longer than 7 days at start of screening. Previous treatment for TB includes, but is not limited to, gatifloxacin, amikacin, cycloserine, rifabutin, kanamycin, para-aminosalicylic acid, rifapentine, thioacetazone, capreomycin, quinolones, thioamides, and metronidazole. 14. Any diseases or conditions in which the use of the standard TB drugs or any of their components is contra-indicated, including but not limited to allergy to any TB drug, their component or to the IMP. 15. Use of any drug within 30 days prior to randomisation known to prolong QTc interval (including, but not limited to, amiodarone, amitriptyline, bepridil, chloroquine, chlorpromazine, cisapride, clarithromycin, disopyramide dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, pimozide, procainamide, quinacrine, quinidine, sotalol, sparfloxacin, thioridazine). 16. Use of systemic glucocorticoids within one year of start of screening (inhaled or intranasal glucocorticoids are allowed). 17. Subjects recently started or expected to need to start anti-retroviral therapy (ART) within 1 month after randomization. Subjects may be included who have been on ARTs for greater than 30 days prior to start of screening, or who are expected to start ART greater than 30 days after randomization. Laboratory Abnormalities 18. Subjects with the following toxicities at screening as defined by the enhanced Division of Microbiology and Infectious Disease (DMID) adult toxicity table (November 2007), where applicable: * creatinine grade 2 or greater (\>1.5 times upper limit of normal \[ULN\]); * creatinine clearance (CrCl) level less than 30 mLs/min according to the Cockcroft-Gault Formula; * haemoglobin grade 4 (\<6.5 g/dL); * platelets grade 3 or greater (under 50x109 cells/L/ 50 000/mm3); * serum potassium less than the lower limit of normal for the laboratory. This may be repeated once; * aspartate aminotransferase (AST) grade 3 or greater (≥3.0 x ULN) ; * alanine aminotransferase (ALT) grade 3 or greater (≥3.0 x ULN); * alkaline phosphatase (ALP): * grade 4 (\>8.0 x ULN) to be excluded; * grade 3 (≥3.0 - 8.0 x ULN) must be discussed with and approved by the sponsor Medical Monitor; * total bilirubin: * 2.0 x ULN, when other liver functions are in the normal range * 1.50 x ULN when accompanied by any increase in other liver function tests subjects with total bilirubin \> 1.25 x ULN and accompanied by any increase in other liver function tests must be discussed with the sponsor medical monitor before enrollment