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End to killer TB? Scientists identify an enzyme that may hold clue

Photo: Siddharth Kankaria/Research Matters

Tuberculosis has emerged as a major health concern across the world with 10.4 million reported cases and 1.8 million deaths in 2015 alone. Although medical science has remarkably improved the situation with the discovery of effective drugs, treating TB is still a major challenge owing to long treatment duration (6–9 months), evolution of drug-resistant strains of TB bacteria Mycobacterium tuberculosis, frequent TB infections among patients with decreased immunity and lack of efficient preventive mechanisms. Across the globe, scientists are on a continuous search for effective strategies that help in fighting against TB bacteria.

Now, based on a new study, a group of scientists at Dr. Reddy’s Institute of Life sciences (DRILS) have proposed that “chorismate mutase”, an enzyme present in the TB bacteria could be a potential target for new drugs, which they believe could potentially help in controlling tuberculosis. Led by Prof. Manojit Pal, Prof. Parimal Misra and Dr. Gopalakrishnan, an interdisciplinary group of scientists from Biology, Medicinal Chemistry and Molecular modelling at DRILS, have discovered that inhibiting the action of chorismate mutase, responsible for producing critical amino acids holds the key to killing these bacteria.

Most bacteria spend about 90% of their energy on synthesizing proteins using different types of amino acids produced in their body that act as building blocks. Of the many pathways that generate amino acids, the ‘shikimate pathway’ is one. “The shikimate pathway is a vital metabolic pathway for the formation of essential aromatic amino acids such as tyrosine and phenylalanine, which are required for the survival of the Mycobacterium”, explains Prof. Pal.

“Chorismate mutase, an enzyme, plays a key role in the biosynthesis of these amino acids. By targeting this enzyme and inhibiting this pathway, one can block the formation of these critical amino acids, and thus kill the bacterium”, says Prof. Pal, explaining the modus operandi. Since this pathway is absent in humans, any new drug that targets chorismate mutase in Mycobacterium, would cause no side effects.

This research, the researchers claim, is the first to identify the lead of inhibiting the said enzyme. “While some initial research in chemical biology, biochemistry and structural biology of chorismate mutase exists, nothing has been reported on this enzyme being the pharmacological target for TB”, claims Prof. Pal. Consequently, there are no major inhibitors of this enzyme reported so far. “Our project is progressing with some interesting results”, he adds.

The researchers have also identified a small molecule, which may have the potential to inhibit chorismate mutase at micromolar concentration and could kill the bacteria at a dose comparable to the marketed TB drug Isoniazid. Funded by the Department of Biotechnology (DBT), through the Centre of Excellence Grant, further research on this might emerge as a breakthrough in our fight against tuberculosis. “This is too early a stage to draw any conclusions about a new drug though we have an interesting lead”, says Prof. Seyed Ehtesham Hasnain who is the overall Project Investigator.

“Such studies on tuberculosis with focus on translational science is an important aspect of the institute’s mission”, emphasises Dr. A. Venkateswarlu, Director of DRILS.

“Currently, our group is working on enhancing the action of this lead molecule at low dosages and improve its efficiency”, signs off Prof. Pal talking about the future of this work.