Levofloxacin

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Levofloxacin is a second-generation fluoroquinolone and is the levo isomer of the racemate ofloxacin. Ofloxacin and levofloxaxin were synthesized and developed by scientists at Daiichi Seiyaku.Daiichi, working with Johnson & Johnson, obtained FDA approval in 1996 under the brand name Levaquin to treat bacterial sinusitus, bacterial exacerbations of bronchitis, community-acquired pneumonia, uncomplicated skin infections, complicated urinary tract infections, and acute pyelonephritis. Levofloxacin is on the World Health Organization's List of Essential Medicines.

Meropenem / Clavulanate

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Beta-lactam antibiotics are ineffective against Mycobacterium tuberculosis, being rapidly hydrolyzed by the chromosomally encoded blaC beta-lactamase. The carbapenem class of b-lactams are very poor substrates for BlaC. Meropenem and clavulanate are US FDA–approved drugs and could potentially be used to treat patients with currently untreatable disease.

Clofazimine

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NC-003-(C-J-Pa-Z) A Phase 2 Trial to Evaluate the Early Bactericidal Activity, Safety and Tolerability of the Following: 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, and Clofazimine Alone; in Adult Patients With Newly Diagnosed, Smear-Positive Pulmonary Tuberculosis.

Trisubstituted benzimidazoles

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Trisubstituted benzimidazoles have demonstrated potency against Gram-positive and Gram-negative pathogens. Previously, a library of novel trisubstituted benzimidazoles was constructed for high throughput screening, and compounds were identified that exhibited potency against M. tuberculosis H37Rv and clinical isolates, and were not toxic to Vero cells. A new series of 2-cyclohexyl-5-acylamino-6-N, N-dimethylaminobenzimidazoles derivatives has been developed based on SAR studies. Screening identified compounds with potency against M. tuberculosis.

Nitazoxanide

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This is a prospective randomized two-arm 14-day, early bactericidal activity study in treatment-naive, drug-susceptible patients with uncomplicated pulmonary tuberculosis (TB). The study will be conducted at the GHESKIO Centers in Port au Prince Haiti. Twenty patients will be randomized to receive NTZ 1 gram orally twice daily for 14 days. Ten patients will be randomized as positive controls to receive standard 4 drug tuberculosis therapy with isoniazid (H), rifampin (R), ethambutol (E), and pyrazinamide (PZA).

Thioridazine

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The repurposing of existing drugs is being pursued as a means by which to accelerate the development of novel regimens for the treatment of drug-susceptible and drug-resistant tuberculosis (TB). In the current study, we assessed the activity of the antipsychotic drug thioridazine (T), in combination with the standard regimen in a well validated murine TB model. Single-dose and steady-state pharmacokinetic studies were performed in BALB/c mice to establish human-equivalent doses of T.

HMG-CoA Reductase Inhibitors

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TB remains one of the leading causes of deaths by infectious diseases worldwide. The need to develop new, improved treatments remains urgent, and the repurposing of existing drugs represents a possible shortcut to market. Recently, there has been significant interest in host-directed adjuvant therapy to enhance bacillary killing. HMG-CoA reductase inhibitors (statins), which are among the most commonly prescribed drugs, have immunomodulatory properties and improve clinical outcomes of bacterial infections.

Rifampicin

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Rifampin is a pivotal drug for the treatment of tuberculosis. The U.S. Food and Drug Administration approved rifampin in 1971 and several trials showed that rifampin-containing regimens were very effective. In combination with pyrazinamide, it became possible to shorten the duration of treatment to 6 months. Virtually all of the studies that support these recommendations used a 10 mg/kg dose of rifampin , but a dose-finding study with an assessment of the maximum tolerated dose was never performed.

Macozinone (MCZ, PBTZ-169)

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PBTZ169 is a piperazinobenzothiazinone derivative optimized by medicinal chemistry from the lead BTZ043. PBTZ169 has several advantages compared to BTZ043, amongst which are easier chemical synthesis, due to the absence of chiral centers, low cost of goods and better pharmacodynamics. PBTZ169 covalently inhibits DprE1, an enzyme essential for the biosynthesis of key cell wall components. The drug has additive effects with many TB therapeutic agents, both marketed and in development, and has synergic effects with bedaquiline and clofazimine in preclinical models.

SPR-113

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SPR113 shows excellent anti-mycobacterial activity in an in vitro system of Mtb infected human macrophages with EC50 of < 50nM against MDR- and XDR-TB strains. SPR113 also shows a dose dependent in vivo efficacy in an MDR-TB infected murine model. The compound has very good oral and IV exposure in mice, shows stability in liver microsomes, is very selective with no CYP or hERG activity.

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