The trial will evaluate the extended bactericidal activity of 14 consecutive days of oral administration of TMC207 plus PA-824 plus Pyrazinamide plus Clofazimine, TMC207 plus PA-824 plus Pyrazinamide, TMC207 plus PA-824 plus Clofazimine alone, TMC207 plus Pyrazinamide plus Clofazimine, Pyrazinamide alone, Clofazimine alone, and standard first line TB treatment as per South African TB Guidelines (Rifafour e-275) as determined by the rate of change of log CFU per ml sputum over the time period Day 0-14 in participants with smear positive pulmonary tuberculosis (TB). A control group will receive standard treatment.

Inclusion Criteria:

• 1. Provide written, informed consent prior to all trial-related procedures including HIV testing.

  2. Male or female, aged between 18 and 65 years inclusive.

  3. Body weight (in light clothing and with no shoes) between 40 and 90 kg, inclusive.

  4. Newly diagnosed, previously untreated, sputum smear-positive pulmonary TB.

  5. A chest X-ray picture which in the opinion of the Investigator is compatible with TB.

  6. Sputum positive GeneXpert or TB Smear from TB clinic or site initial diagnosis

  7. Sputum positive on direct microscopy for acid-fast bacilli (at least 1+ on the IUATLD/WHO scale).

  8. Ability to produce an adequate volume of sputum as estimated from a spot assessment (estimated 10 ml or more overnight production).

  9. Be of non-childbearing potential or using an effective method of birth control as defined as:

Non-childbearing potential:

1. Subject - Not heterosexually active or practice sexual abstinence or
2. Female subject/sexual 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
3. Male subject/sexual partner - vasectomised or has had a bilateral orchidectomy minimally three month prior to screening

Effective birth control methods:

1. Double barrier method which can include a male condom, diaphragms, cervical cap, or female condom or
2. Barrier method combined with hormone based contraceptives or an intra-uterine device for the female partner and are willing to continue practicing birth control methods throughout treatment and for 12 weeks (male participants) or 6 months (female participants) after the last dose of study medication or discontinuation from study medication in case of premature discontinuation

(Note: Hormone-based contraception alone may not be reliable when taking IMP; therefore, hormone-based contraceptives alone cannot be used by female participants to prevent pregnancy).

Exclusion Criteria:

1. Evidence of clinically significant (as judged by the investigator), metabolic, gastrointestinal, cardiovascular, musculoskeletal, ophthalmological, pulmonary, neurological, psychiatric or endocrine diseases, malignancy, or other abnormalities (other than the indication being studied) including malaria.

2. Poor general condition where any delay in treatment cannot be tolerated per discretion of the Investigator.

3. A history of previous TB.

4. Clinically significant evidence of extrathoracic TB (miliary TB, abdominal TB, urogenital TB, osteoarthritic TB, TB meningitis), as judged by the Investigator.

5. History of allergy to the IMP or related substances.

6. Isoniazid-resistant and/or Rifampicin-resistant bacteria detected with a sputum specimen collected within the pre-treatment period and tested at the study laboratory.

7. Known or suspected, current or history of within the past 2 years, alcohol or drug abuse, that is, in the opinion of the Investigator, sufficient to compromise the safety or cooperation of the participant.

8. HIV infected participants:

   1. having a CD4+ count <200 cells/µL;
   2. or having received antiretroviral therapy medication within the last 90 days;
   3. or having received oral or intravenous antifungal medication within the last 90 days;
   4. or with an AIDS-defining opportunistic infection or malignancies (except pulmonary TB).

9. Having participated in other clinical studies with investigational agents within 8 weeks prior to trial start.

10. Significant cardiac arrhythmia requiring medication.

11. Participants with the following at screening. For ECGs, central cardiology overread and the mean of triplicate reading must be used:

    1. Marked prolongation of QT/QTc interval, e.g., confirmed demonstration of QTcF (Fridericia correction) or QTcB (Bazett correction) interval >450 ms at screening;
    2. History of additional risk factors for Torsade de Pointes, e.g., heart failure, hypokalemia, family history of Long QT Syndrome;
    3. Use of concomitant medications that prolong the QT/QTc interval (see exclusion criterion 19 and disallowed medications;
    4. Pathological Q waves (defined as >40ms or depth >0.4-0.5mV);
    5. ECG evidence of ventricular pre-excitation;
    6. ECG evidence of complete or incomplete left bundle branch block or right bundle branch block;
    7. ECG evidence of second or third degree heart block;
    8. Intraventricular conduction delay with QRS duration >120ms;
    9. Bradycardia as defined by sinus rate <50bpm.

12. Females who are pregnant, breast-feeding, or planning to conceive a child within 6 months of cessation of treatment. Males planning to conceive a child within twelve weeks of cessation of treatment.

13. Diabetes Mellitus requiring insulin.

14. History of lens opacity.

15. For males, any history of a clinically significant abnormality in the reproductive system.

    Specific Treatments

16. Previously received treatment with Clofazimine, TMC207 or PA-824.

17. Treatment received with any drug active against MTB within the 3 months prior to Visit 1 (e.g. isoniazid, ethambutol, amikacin, cycloserine, fluoroquinolones, rifabutin, rifampicin, streptomycin, kanamycin, para-aminosalicylic acid, rifapentine, pyrazinamide, thioacetazone, capreomycin, thioamides, metronidazole).

18. 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.

19. Concomitant use of any drug known to prolong QTc interval (including amiodarone, bepridil, chloroquine, chlorpromazine, cisapride, clarithromycin, cyclobenzaprine, disopyramide dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, pimozide, procainamide, quinidine, sotalol, sparfloxacin, thioridazine).

20. Use of any drugs or substances within 30 days prior to dosing known to be strong inhibitors or inducers of cytochrome P450 enzymes (such as quinidine, tyramine, ketoconazole, testosterone, quinine, gestodene, metyrapone, phenelzine, doxorubicin, troleandomycin, cyclobenzaprine, erythromycin, cocaine, furafylline, cimetidine, dextromethorphan). Exceptions may be made for participants that have received 3 days or less of one of these drugs or substances, if there has been a wash-out period before administration of IMP equivalent to at least 5 half-lives of that drug or substance.

21. Use of any therapeutic agents known to alter any major organ function (e.g., barbiturates, opiates, phenothiazines, cimetidine) within 30 days prior to dosing. Exceptions for opiate and pain killer use for cough or underlying disease may be made at investigator discretion.

    Based on Laboratory Abnormalities

22. Participants with the following toxicities at screening as defined by the enhanced Division of Microbiology and Infectious Disease (DMID) adult toxicity table (November 2007):

    1. creatinine grade 2 or greater (>1.5 times upper limit of normal [ULN]);
    2. lipase grade 3 or greater (>2.0 x ULN);
    3. hemoglobin grade 4 (<6.5 g/dL);
    4. platelets grade 2 or greater (under 50x109 cells/L);
    5. serum potassium grade 2 or greater (<3.5 mEq/L);
    6. aspartate aminotransferase (AST) grade 3 (≥3.0 x ULN) to be excluded;
    7. alanine aminotransferase (ALT) grade 3 (≥3.0 x ULN) to be excluded;
    8. alkaline phosphatase (ALP) grade 4 (>8.0 x ULN) to be excluded, grade 3 (≥3.0 x ULN) must be discussed with the sponsor Medical Monitor;
    9. total bilirubin grade 3 or greater (>2.0 x ULN, or >1.50 x ULN when accompanied by any increase in other liver function test) to be excluded, grade 2 (>1.50 x ULN, or >1.25 x ULN when accompanied by any increase in other liver function test) must be discussed with the sponsor Medical Monitor.