TMC207: the first compound of a new class of potent anti-tuberculosis drugs

Abstract

Disease caused by Mycobacterium tuberculosis continues as a global epidemic: over 2 billion people harbor latent TB infection, and more than 9 million new TB cases, of whom 500,000 are multidrug-resistant (MDR), and nearly 2 million deaths are estimated to occur each year. New drugs are required to shorten treatment duration of drug-sensitive TB and for the treatment of MDR-TB. TMC207 is a first-in-class diarylquinoline compound with a novel mechanism of action, the inhibition of bacterial ATP synthase, and potent activity against drug-sensitive and drug-resistant TB. It has bactericidal and sterilizing activity against M. tuberculosis and other mycobacterial species, but little activity against other bacteria. In a Phase II efficacy study conducted in patients with MDR-TB taking TMC207 plus a standard background regimen, the drug appeared to be safe and well tolerated, and showed significant efficacy after 2 months of treatment with conversion rates of sputum culture of 48% (vs 9% in the placebo group). Given the product development partnership between Tibotec and the TB Alliance, the strategies of using TMC207 in shorter first-line regimens or using it in second-line regimens for drug-resistant M. tuberculosis infections are both being pursued. No clinical data of TMC207 in TB patients with HIV coinfection have been published; drug–drug interaction studies with antiretrovirals are being conducted. Finally, the remarkable sterilizing capacity of TMC207 also makes it an attractive drug in the strategy of TB elimination. Current and future studies will determine the role of TMC207 in a shortened treatment regimen for drug-sensitive TB, a more effective and better-tolerated regimen for MDR-TB, the treatment of latent TB infection, and intermittent-TB treatment regimens.

Bedaquiline: a new weapon against MDR and XDR-TB

“…In contrast to several other bacteria, which can produce sufficient ATP by substrate-level phosphorylation and tolerate deletion of ATP synthase, ATP synthase has been proven to be essential for optimal growth in M. tuberculosis. Mutations in subunit c conferring resistance to TMC207 suggest a binding site in the central region of subunit c. 12,15,16 After oral dose of 400 mg of, the t max was found to be 4 hours, the C max was 5.5 mg/L after 400 mg/day, and the AUC 0-24 was 65 mg h/L. Based on these data, the clearance was around 6.2 L/h.…”

“…It is found to active within macrophages, and is a promising agent in shortening the duration of anti-TB treatment. 12,14,15 It has unique and specific antimycobacterial activity. It acts by targeting subunit c of the ATP synthase of M. tuberculosis, leading to inhibition of the proton pump activity of the ATP synthase.…”

“…A significant bactericidal activity has been reported at days 4-7 after starting the treatment. 12,15,17,20 Resistance has been found to be associated with two point mutations: D32V and A63P. This region of the gene encodes the membrane-spanning domain of the ATP synthase c subunit.…”

“…Incidence of nausea was significantly higher in bedaquiline group. 12,27,28 However, only a limited number of patients have been exposed to this drug, so that the full side-effect profile is unclear. 15 There are two important black box warnings for the use of bedaquiline i.e.…”

“…Important precautions and contraindicated are 12,27,28,30,31 ECG should be done before starting treatment and at least 2, 12, and 24 weeks after starting therapy.…”