A seven year search has led an Indian group of chemical and structural biologists to discover what they believe might someday become an effective tuberculosis drug.
The compound developed by Rajesh Gokhale at the National Institute of Immunology (NII) in New Delhi and his co-workers attacks four of the bacterium's crucial metabolic pathways at the same time — somewhat like the proverbial one stone killing four birds.
The team claims that their finding that the compound binds to more than one target challenges the 'one disease – one drug – one target' paradigm that has dominated thinking in the pharmaceutical industry for the past few decades1.
The molecule designed and tested by the Indian group destroys the tuberculosis bacilli (Mycobacterium tuberculosis) in a test-tube. "It is still years away from being tested on humans," admits Rajan Sankaranarayanan, a structural biologist and Gokale's collaborator at the Centre for Cellular and Molecular Biology (CCMB) in Hyderabad.
"Developing a single chemical entity that could simultaneously target a family of enzymes is a better approach than designing a TB drug against a single target" says Gokhale, who is also a Howard Hughes Medical Institute international research scholar. He believes that if and when developed into a drug, the compound could replace the cocktail of drugs that TB patients must currently take for treatment.
M. tuberculosis does not cause disease in everyone it infects even though it may reside inside the host for several years. The quest to unravel the mystery of what makes the organism remain dormant for years led Gokhale and his colleagues to zero in on the fatty 'coat' worn by the organism.
Since 2001 his group — by combining tools of biochemistry, structural and molecular biology — was trying to figure out how the organism builds the lipid (fat) layer and the role it played in development of the disease.
Their research in 2004 led to the discovery of several genes in the TB genome where each gene is involved directly in different pathway of making the lipid layer using a family of enzymes called long-chain fatty acyl-AMP ligases (FAALs). Since the different pathways involved overlapping enzymes "we thought we could design a single molecule targeting the multiple pathways," Gokhale said.
"Because FAALs in M.tuberculosis are crucial nodes in the biosynthetic network of virulent lipids, inhibitors directed against these proteins provide a unique multi-pronged approach to simultaneously disrupting several pathways," the authors report. Gokhale collaborated with Sankaranarayanan, to design and examine the three-dimensional structure of the molecule.
"Even if you partially inhibit multiple pathways with this molecule it actually becomes much broader than hitting (the TB bacillus) at one place," Gokhale said. "That is what we wanted to demonstrate in our latest study."
"In a test-tube it works — the molecule inhibits these enzymes. In vivo we have not demonstrated because we do not have an animal model where you can have dormant bacteria," Gokhale said.
Gokhale's in vitro experiment no doubt has provided the spark that made him think about how to translate that finding into a drug. "Ours is a new concept and we have unambiguously demonstrated the science behind it," he told Nature India. "How we can convert it into a drug is something we are discussing with companies."
That may be a tough task since several challenges have to be overcome, according to researchers familiar with the drug development process.
"It is an interesting paper and a fitting summary of the pioneering work this group has been involved in over the many years," says Tanjore Balganesh, head of research at AstraZeneca in Bangalore the only pharmaceutical company in the world with a research programme in India totally dedicated to TB. "Having said that, the concept of a single drug, launching a drug discovery programme on the molecule described, or the validity of such a series of targets are different aspects of the drug discovery paradigm," he told Nature India.
The paper was also read with interest at Global Alliance for TB Drug Development, a not-for-profit organization based in New York.
"Gokhale is proposing to inhibit not one target, but a whole family of related targets," says Gerry Waters, senior director at the Alliance. "It is a great idea. However many drug developers will still judge the merits of the approach by some of the same concepts normally applied to single-target programs," he told Nature India. "For example, it would be best if at least one of Gokhale's targets is an essential enzyme, meaning that TB cells cannot survive without it."
One other hurdle along the way to drug development stems from the fact that humans have a similar enzyme to the family that Gokhale's team aims to target. So any drug that is developed needs to inhibit the TB enzymes, but not the human enzyme.
The Indian researchers say they are aware of the challenges and admit the road to drug development is not going to be easy. "Right now we want to do a little bit of chemistry on this molecule," Gokhale told Nature India. "We have just signed an agreement with a life sciences company in Kolkata to take it forward."