The problem is that Gokhale's compound will not work in humans. Not willing to set aside seven years of work, he has been knocking on the doors of pharmaceutical companies to see if he can get any takers to help design a less toxic version.
Gokhale is pushing himself because he knows if he can design a single drug that is safe and effective, it might one day replace the costly cocktail of drugs that people with tuberculosis must currently take to cure their disease.
While a drug based on Gokhale's ideas is still years away from human testing, it offers a measure of hope that researchers may one day have more modern pharmaceutical "weapons" that can slow down the tuberculosis (TB) pathogen's relentless assault. According to the World Health Organization, TB remains one of the world's top-ten leading causes of death, killing nearly two million people each year. In Gokhale's native India, it kills roughly 1,000 people each day.
"Right now, tuberculosis patients take a cocktail of four drugs, and each inhibits a single enzyme," said Gokhale, a Howard Hughes Medical Institute international research scholar based at the National Institute of Immunology in New Delhi, India. Gokhale's group shows how they designed the molecule that targets multiple enzymes in Mycobacterium tuberculosis in the January 25, 2009, issue of Nature Chemical Biology. "Targeting several enzymes at the same time is a much more efficient approach. Theoretically, patients wouldn't have to take several drugs, they could just take one."
The multi-drug regimen is a major problem for several reasons. It requires TB patients to manage taking four drugs exactly as prescribed over six to nine months. If patients don't take the full course of the medicines, the TB bacteria may develop resistance to the drugs and become even more difficult to treat. To reduce that risk, many countries require that patients go to a clinic so a healthcare professional can watch them take the medication and ensure they are complying with their drug-treatment regimen. This is both expensive and time consuming. Gokhale said that a single drug that targets multiple pathways could save time and money by eliminating the need to take so many drugs over such a long period of time.
To create their new compound, Gokhale and his colleagues exploited an evolutionary quirk in the way Mycobacterium tuberculosis builds the lipid layer that coats its surface. Unlike other organisms, M. tuberculosis displays a suite of complex lipids on its outer membrane. Some scientists have suggested that these long lipid molecules contribute to the bacteria's ability to maintain long-term infections by confusing the host's immune system.
"The complex lipids displayed by Mycobacterium tuberculosis are a big factor in its pathogenicity and virulence," Gokhale said. "But what was not known is how they were made by the organism."
For the past seven years, Gokhale and his colleagues have studied the intricate metabolic pathways that Mycobacterium tuberculosis employs to build complex lipids. He has come to regard the TB bacteria as a "chemical factory" where complex machines, in the form of enzymes, work together to link simple building blocks—called fatty acids—into long chains. In 2004, Gokhale and his colleagues found a new class of enzymes that are critical for an early phase of the lipid-building process. Called fatty acyl-AMP ligases (FAALs), these enzymes tweak fatty acids so that a second class of enzymes can string them together like bulbs on a strand of Christmas lights.
In their most recent study, Gokhale and his colleagues show that particular molecules that inhibit FAALs also inhibit other, similarly-shaped enzymes involved in the assembly line that is lipid use and degradation. These enzymes are required during the life cycle of the TB bacterium in the humans. "A major challenge has been to develop drugs that could target different stages disease," Gokhale said. "Since this single molecule could potentially grind the assembly line to a halt at different stages of infection, this approach provides tremendous opportunity to develop unique antituberculosis drugs."
Gokhale has collaborated with a colleague at a colleague at the Centre for Cellular and Molecular Biology in Hyderabad, Rajan Sankaranarayanan, to examine the three-dimensional structure of the molecule. This will give his group the opportunity to modify the molecule or develop a new one that is less toxic and better targets the TB bacteria. Gokhale said that the drug industry is finally waking up to the idea that a single drug can work on multiple metabolic pathways, rather than making a molecule that acts in a very specific way on a single target.
"The 'one disease–one drug–one target' paradigm that has dominated thinking in the pharmaceutical industry for the past few decades is now being increasingly challenged by the discovery of compounds that bind to more than one target," Gokhale said. "That's the direction we're heading in trying to develop a single chemical entity that could simultaneously target a family of enzymes in TB."
Andrea Widener | EurekAlert!
Scientists uncover the role of a protein in production & survival of myelin-forming cells
19.07.2018 | Advanced Science Research Center, GC/CUNY
NYSCF researchers develop novel bioengineering technique for personalized bone grafts
18.07.2018 | New York Stem Cell Foundation
A new manufacturing technique uses a process similar to newspaper printing to form smoother and more flexible metals for making ultrafast electronic devices.
The low-cost process, developed by Purdue University researchers, combines tools already used in industry for manufacturing metals on a large scale, but uses...
For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.
To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...
For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.
Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...
Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.
A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...
Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.
"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....
13.07.2018 | Event News
12.07.2018 | Event News
03.07.2018 | Event News
20.07.2018 | Power and Electrical Engineering
20.07.2018 | Information Technology
20.07.2018 | Materials Sciences