Abstract
The latest WHO report estimates about 1.6 million global deaths annually from TB, which is further exacerbated by drug-resistant (DR) TB and comorbidities with diabetes and HIV. Exiguous dosing, incomplete treatment course, and the ability of the tuberculosis bacilli to tolerate and survive current first-line and second-line anti-TB drugs, in either their latent state or active state, has resulted in an increased prevalence of multidrug-resistant (MDR), extensively drug-resistant (XDR), and totally drug-resistant TB (TDR-TB). Although a better understanding of the TB microanatomy, genome, transcriptome, proteome, and metabolome, has resulted in the discovery of a few novel promising anti-TB drug targets and diagnostic biomarkers of late, no new anti-TB drug candidates have been approved for routine therapy in over 50 years, with only bedaquiline, delamanid, and pretomanid recently receiving tentative regulatory approval. Considering this, alternative approaches for identifying possible new anti-TB drug candidates, for effectively eradicating both replicating and non-replicating Mycobacterium tuberculosis, are still urgently required. Subsequently, several antibiotic and non-antibiotic drugs with known treatment indications (TB targeted and non-TB targeted) are now being repurposed and/or derivatized as novel antibiotics for possible use in TB therapy. Insights gathered here reveal that more studies focused on drug-drug interactions between licensed and potential lead anti-TB drug candidates need to be prioritized. This write-up encapsulates the most recent findings regarding investigational compounds with promising anti-TB potential and drugs with repurposing potential in TB therapy.
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NCT02684240 Cg- A 14 day early bactericidal activity study of nitazoxanide for the treatment of tuberculosis. https://clinicaltrials.gov/ct2/show/NCT02684240. Accessed Jan 2020
NCT02754765 Cg- Evaluating newly approved drugs for multidrug-resistant TB (endTB): A clinical trial. https://clinicaltrials.gov/ct2/show/NCT02754765. Accessed Jan 2020
NCT02774993 Cg- Doxycycline and the modulation of host immunopathology in human pulmonary tuberculosis: A pilot study. https://clinicaltrials.gov/ct2/show/NCT02774993. Accessed Jan 2020
NCT02781909 Cg- Pilot study to estimate the potential efficacy and safety of using adjunctive ibuprofen for the treatment of XDR tuberculosis. https://clinicaltrials.gov/ct2/show/NCT02781909. Accessed Jan 2020
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NCT03033329 Cg- A randomized, double-blind, placebo controlled three-part study of the safety, tolerability, and pharmacokinetics of MRX 4 administered intravenously to healthy volunteers in single ascending and multiple ascending dose cohorts, and bioavailability of oral MRX-4 versus intravenous administration. https://clinicaltrials.gov/show/NCT03033329. Accessed Jan 2020
NCT03086486 Cg- A phase 3 partially-blinded, randomized trial assessing the safety and efficacy of various doses and treatment durations of linezolid plus bedaquiline and pretomanid in participants with pulmonary infection of either extensively drug-resistant tuberculosis (XDR-TB), pre-XDR-TB or treatment intolerant or non-responsive multi-drug resistant tuberculosis (MDR-TB). https://clinicaltrials.gov/ct2/show/NCT03086486. Accessed Jan 2020
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NCT03174184 Cg- A phase 2a study of the early bactericidal activity of rifampin (RIF) in combination with meropenem plus amoxicillin/clavulanate among adults with rifampin-resistant or rifampin-susceptible pulmonary tuberculosis. https://clinicaltrials.gov/ct2/show/NCT03174184. Accessed Jan 2020
NCT03199313 Cg- A phase 1, randomized, double-blind, placebo-controlled, single ascending dose study to evaluate the safety, tolerability, and pharmacokinetics of sutezolid in healthy adult subjects. https://clinicaltrials.gov/ct2/show/NCT03199313. Accessed Jan 2020
NCT03199339 Cg- Phase 1, partially-blind, placebo controlled randomized, combined SAD with food effect cohort and MAD and DDI Study to evaluate safety, tolerability, PK and PK interaction between TBA-7371 with midazolam and bupropion in healthy subjects. https://clinicaltrials.gov/ct2/show/NCT03199339. Accessed Jan 2020
NCT03237182 Cg- The individualized M(X) Drug-resistant TB treatment strategy study a strategy to improve treatment outcomes in patients with drug-resistant TB. https://clinicaltrials.gov/ct2/show/NCT03237182. Accessed Jan 2020
NCT03338621 Cg- An open-label, partially randomized trial to evaluate the efficacy, safety and tolerability of a 4-month treatment of bedaquiline plus pretomanid plus moxifloxacin plus pyrazinamide (BPaMZ) compared to a 6-month treatment of hrze/hr (control) in adult participants with drug-sensitive smear-positive pulmonary tuberculosis (DS-TB) and a 6-month Treatment of BPaMZ in adult participants with drug resistant, smear-positive pulmonary tuberculosis (DR-TB). https://clinicaltrials.gov/ct2/show/NCT03338621. Accessed Jan 2020
NCT03545373 Cg- Randomised controlled clinical trial investigating benefits of using response to broad spectrum antibiotics as an exclusion diagnostic for tuberculosis (TB) in primary care adult patients versus risk of antimicrobial resistance (AMR). https://clinicaltrials.gov/ct2/show/NCT03545373. Accessed Jan 2020
NCT03563599 Cg- An open-label randomized study to evaluate the early bactericidal activity, safety, tolerability, and pharmacokinetics of multiple oral doses of telacebec (Q203) in treatment-naïve patients with newly diagnosed drug-sensitive sputum smear-positive pulmonary tuberculosis. https://clinicaltrials.gov/ct2/show/NCT03563599. Accessed Jan 2020
NCT03758612 Cg- A phase 1, partially-blinded, placebo-controlled, randomized, single ascending dose (SAD) with a food effect cohort study to evaluate the safety, tolerability, and pharmacokinetics of TBI-223 in healthy adult participants. https://clinicaltrials.gov/ct2/show/NCT03758612. Accessed Jan 2020
NCT04062201 Cg- An open label, randomized controlled trial to establish the efficacy and safety of a study strategy consisting of 6 months of bedaquiline (BDQ), delamanid (DLM), and linezolid (LNZ), with levofloxacin (LVX) and clofazimine (CFZ) compared to the current south african standard of care (control strategy) for 9 months for the treatment of rifampicin resistant tuberculosis (RR-TB). https://clinicaltrials.gov/ct2/show/NCT04062201. Accessed Jan 2020
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The first author appreciates North-West University for Post-Doctoral fellowship.
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Adeniji, A.A., Knoll, K.E. & Loots, D.T. Potential anti-TB investigational compounds and drugs with repurposing potential in TB therapy: a conspectus. Appl Microbiol Biotechnol 104, 5633–5662 (2020). https://doi.org/10.1007/s00253-020-10606-y
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DOI: https://doi.org/10.1007/s00253-020-10606-y