World Tuberculosis Day was observed last week. The disease accounts for nearly 1.5 million deaths worldwide every year, most of them in developing countries, including India. According to the Global Tuberculosis Report published by the World Health Organisation, India topped the list of seven countries that accounted for 64% of the 10.4 million new tuberculosis (TB) cases worldwide in 2016. On March 13, Prime Minister Narendra Modi launched the ‘TB-free India’ campaign to eradicate the disease from the country by 2025.
Tuberculosis is not a new disease. Nor is it untreatable. In fact, there are several drugs that cure people suffering from it. Vaccines too, are available to prevent the occurrence of tuberculosis. In spite of all these, the disease continues to claim millions of lives across the world. One of the reasons is the regular emergence of newer strains of Mycobacterium tuberculosis, the bacterium responsible for the disease, that are resistant to some of the most commonly used existing first-line drugs. At the same time, newer drugs and novel therapeutic approaches have also been discovered over the last few years to fight TB.
The latest success in this effort has been reported by scientists of the Molecular Biophysics Unit at the Indian Institute of Science, Bangalore. This group, led by Prof Avadhesha Surolia and Dr Archita Mishra, has discovered a new drug that has shown substantially improved results in preventing the growth of Mycobacterium tuberculosis (MTB) in the human body compared to existing drugs. To be sure, the drug identified by the group, Pranlukast, is new only so far as it is being used against TB. Pranlukast is an existing FDA-approved molecule used extensively as an anti-asthmatic drug. Surolia’s group has found that this molecule is not only effective in preventing the growth of MTB, but also blocks the process through which the bacterium makes its stay possible inside the human body.
Surolia points out that one of the difficulties in treating TB is the ability of the MTB bacterium to manipulate the human body’s defence mechanism in its favour.
MTB has thick cell walls, which is impermeable to a large number of drugs. But what makes it so potent is its ability to deceive the immune system. Unlike most other foreign microorganisms that enter the human body, the macrophages, a type of white blood cells that act as the first line of immunity, is unable to kill MTB. Instead, the bacterium is able to manipulate them in such a way that they actually become conducive for its existence and growth.
The key to sustenance and pathogenesis of MTB inside the human body is an amino acid called arginine. Inhibiting the production of arginine is one certain way of preventing the growth of MTB. Instead of exploring the development of new compounds, Surolia’s group looked at existing molecules that could inhibit the production of arginine. It also identified the most effective area on the enzyme for this molecule to bind.
The group started hunting the FDA-approved drug library for a suitable molecule. They screened as many as 1,400 existing drugs of which 34 with desired properties were isolated. Of these, only two were found to be effective in inhibiting the production of the enzyme as well as binding at the right place. Pranlukast happened to be one of them.
Pranlukast showed remarkable effectiveness in stopping the growth of MTB bacteria in macrophage culture and also in the mouse model of TB. For treating the disease, doctors usually use a combination of three drugs. The scientists at IISc replaced one of the drugs, Ethambutol, in one such combination, with Pranlukast, while retaining the other two commonly used drugs, Rifampicin and Isoniazid. The result obtained, in terms of the ability to prevent the growth of MTB, was “much better” than the original combination. The scientists have reported their findings in the EMBO Molecular Medicine, an open-source peer-reviewed journal.
Since the Pranlukast molecule already has an FDA approval, it would not require the Stage I toxicology tests to be done all over again, and can be fast-tracked to the market.
The research: Finding a drug molecule that inhibits the growth of TB-causing bacterium
Researchers: Archita Mishra, Avadhesha Surolia and team Indian Institute of Science, Bangalore