Synthetic investigational new drugs for the treatment of tuberculosis

ABSTRACT

Introduction: Tuberculosis (TB) is a major global health concern. And while there are treatments already on the market, there is a demand for new drugs that are effective and safe against Mycobacterium tuberculosis, which reduce the number of drugs and the duration of treatment in both drug-susceptible TB and multidrug-resistant TB (MDR-TB).

Area covered: This review covers promising novel investigational TB drugs that are currently under development. Specifically, the authors review the efficacy of novel agents for the treatment of TB in preclinical, phase I and phase II clinical trials. The authors also review the safety and tolerability profiles of these drugs.

Expert opinion: Bedaquiline and delamanid are the most promising novel drugs for the treatment of MDR-TB, each having high efficacy and tolerability. However, the best regimen for achieving better outcomes and reducing adverse drug reactions remains to be determined, with safety concerns regarding cardiac events due to QT prolongation still to be addressed. Pretomanid is a novel drug that potentially shortens the duration of treatment in both drug-susceptible and drug-resistant TB in combination with moxifloxacin and pyrazinamide. Linezolid shows marked efficacy in the treatment of MDR-TB and extensively drug-resistant TB (XDR-TB), but the drug is known to cause significant adverse drug reactions, including peripheral neuropathy, optic neuropathy and myelosuppression. These adverse reactions must be considered prior to prescribing long-term usage of this drug.

KEYWORDS:

• Antitubercular agents
• bedaquiline
• delamanid
• multidrug-resistant tuberculosis
• tuberculosis

Declaration of Interest

This study was funded by the Medical Research Fund of the Samsung Medical Center [SMO1140221]. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Article highlights.

• Bedaquiline is a potent novel drug targeting the adenosine triphosphate proton pump in Mycobacterium tuberculosis, and a treatment period of 6 months in combination with the standard regimen has shown high efficacy and safety.

• Delamanid is a promising novel drug targeting the synthesis of mycobacterial cell wall, and a 6-month treatment period in combination with an optimized background regimen has shown high efficacy and tolerability.

• Pretomanid has potent anti-mycobacterial activity targeting the synthesis of mycobacterial cell wall, and demonstrated high efficacy and safety in combination with moxifloxacin and pyrazinamide.

• Linezolid, the first oxazolidinone agent targeting protein synthesis by binding 23S RNA in the 50S ribosomal subunit of bacteria, has high efficacy against MDR/XDR-TB, but use of this drug is limited by adverse drug reactions such as peripheral neuropathy, optic neuropathy and myelosuppression.

• Development of novel agents could improve TB treatment outcomes and minimize adverse reactions and safety concerns, but the optimal TB regimen has yet to be determined.This box summarizes key points contained in the article.