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IISc's (Indian Institute of Science) latest find could break new ground in the treatment of TB and offer hope to lakhs of patients languishing away.
A group, comprising nine researchers, has discovered a compound that can kill multiple drug-resistant tuberculosis bacteria. With the nation reporting over 1.96 million new TB cases every year, this compound could just be the right weapon to beat the deadly bacteria which have become increasingly hostile to the most potent TB drugs.
The multi-disciplinary research spanning six years and undertaken by three departments of IISc has yielded promising results. Their research shows that targeting a particular protein in the mycobacterium tuberculosis (MTb) -- a common bacteria found in most TB cases -- hinders its growth, thus making the disease curable.
The research was spearheaded by professor V Nagaraja, former chairman, department of microbiology and cell biology and professor S Ramakumar, department of physics. Explaining their breakthrough, Professor Nagaraja says they targeted a Histone-like protein that is an essential component in the DNA of the bacteria. "The protein itself binds to the DNA of the bacteria, condenses it and turns several genes off. We have found a chemical compound that inhibits the protein and hinders growth of the bacteria. The compound binds itself to the DNA of the bacteria and condenses it, thereby turning its genes off. Even mutated bacteria which are highly resistant to drugs can succumb to this compound. Histone-like proteins in bacteria are not usually targeted for drug discovery. This is the first time, not only in the history of IISc, but across the world, that the nucleoid-associated protein of the bacteria has been targeted."
The group found that the HU protein binds the DNA and protects it. But taking away the protein not only breaks it, but it also becomes susceptible to all kinds of degradation. While the group discovered this two years ago, extensive validation and experimentation had to be carried out to confirm their results. While the Physics department helped with crystallography of proteins and computational biology, the department of Biophysics helped with nuclear magnetic resonance (NMR) spectroscopy which found that the SD1 molecule binds to the protein. Biology experiments and mutational analysis were done by the department of Microbiology and Cell Biology.
Underlining that the research is not yet at the level of clinical trials, Professor Ramakumar says, "We have tried it on the cells and we have observed growth hindrance, which means the bacteria do not multiply."
Soumitra Ghosh, PhD student, department of Microbiology and Cell Biology, who has co-authored the paper said in the past small molecules haven't been targeted on big sites. "When we looked into the DNA-binding grove of the protein, we found it had a huge binding site onto which a suitable molecule can attach itself. So we tried, for the first time, to prove a concept that a big pocket can also be targeted. We found a molecule, which is a Stilbene derivative. Stilbene is a diarylethene compound of hydrocarbon that has existed in Chemistry for a while now."
The group first solved the crystal structure of the protein. Then they hit upon the DNA interaction core. "Based on that, we looked for a compound that could fit into the pocket. We did something called In Silico docking or a computational scan of the protein and discovered that SD1 and SD4, both derivatives of Stilebene, were best fits. They both showed high effectiveness against the protein, HU." Ghosh says within a week of treating the bacteria directly with SD1, it was found that the bacteria stopped multiplying and subsequently died.
The paper was co-authored by the professors along with Prof Siddharth P Sarma and PhD students Tuhin Bhowmick, Soumitra Ghosh, Karuna Dixit, Debayan Dey, Varsha Ganesan, Udupi A Ramagopal.
The group has co-authored a paper on their findings which was published in Nature.com - an American website that publishes scientific journals.
A top official in the National Tuberculosis Institute confirmed that most drugs targeted the DNA gyrase and RNA polymerase components of the bacteria. "If the group has found a molecule that can target the Histone-like protein, then it is great news for us. Most TB cases in India go unreported. In about 12 percent of re-treatment cases, multi-drug resistant MTb has been found," he said on condition of anonymity.
Key to new drugs
While the finding is at the most basic and at the lowest end of the drug discovery process, it has the potential to be explored and developed into new classes of TB drugs in combination with other, existing drugs. "The molecule, which kills the bacteria by targeting the protein, has the potential to be tapped for introducing new drugs. We found that when the molecule is administered directly on the bacteria, it takes about a week's time to completely kill it," says Prof Nagaraja.
IISc's killer discovery to fight multiple drug resistant TB bacteria - Bangalore Mirror
A group, comprising nine researchers, has discovered a compound that can kill multiple drug-resistant tuberculosis bacteria. With the nation reporting over 1.96 million new TB cases every year, this compound could just be the right weapon to beat the deadly bacteria which have become increasingly hostile to the most potent TB drugs.
The multi-disciplinary research spanning six years and undertaken by three departments of IISc has yielded promising results. Their research shows that targeting a particular protein in the mycobacterium tuberculosis (MTb) -- a common bacteria found in most TB cases -- hinders its growth, thus making the disease curable.
The research was spearheaded by professor V Nagaraja, former chairman, department of microbiology and cell biology and professor S Ramakumar, department of physics. Explaining their breakthrough, Professor Nagaraja says they targeted a Histone-like protein that is an essential component in the DNA of the bacteria. "The protein itself binds to the DNA of the bacteria, condenses it and turns several genes off. We have found a chemical compound that inhibits the protein and hinders growth of the bacteria. The compound binds itself to the DNA of the bacteria and condenses it, thereby turning its genes off. Even mutated bacteria which are highly resistant to drugs can succumb to this compound. Histone-like proteins in bacteria are not usually targeted for drug discovery. This is the first time, not only in the history of IISc, but across the world, that the nucleoid-associated protein of the bacteria has been targeted."
The group found that the HU protein binds the DNA and protects it. But taking away the protein not only breaks it, but it also becomes susceptible to all kinds of degradation. While the group discovered this two years ago, extensive validation and experimentation had to be carried out to confirm their results. While the Physics department helped with crystallography of proteins and computational biology, the department of Biophysics helped with nuclear magnetic resonance (NMR) spectroscopy which found that the SD1 molecule binds to the protein. Biology experiments and mutational analysis were done by the department of Microbiology and Cell Biology.
Underlining that the research is not yet at the level of clinical trials, Professor Ramakumar says, "We have tried it on the cells and we have observed growth hindrance, which means the bacteria do not multiply."
Soumitra Ghosh, PhD student, department of Microbiology and Cell Biology, who has co-authored the paper said in the past small molecules haven't been targeted on big sites. "When we looked into the DNA-binding grove of the protein, we found it had a huge binding site onto which a suitable molecule can attach itself. So we tried, for the first time, to prove a concept that a big pocket can also be targeted. We found a molecule, which is a Stilbene derivative. Stilbene is a diarylethene compound of hydrocarbon that has existed in Chemistry for a while now."
The group first solved the crystal structure of the protein. Then they hit upon the DNA interaction core. "Based on that, we looked for a compound that could fit into the pocket. We did something called In Silico docking or a computational scan of the protein and discovered that SD1 and SD4, both derivatives of Stilebene, were best fits. They both showed high effectiveness against the protein, HU." Ghosh says within a week of treating the bacteria directly with SD1, it was found that the bacteria stopped multiplying and subsequently died.
The paper was co-authored by the professors along with Prof Siddharth P Sarma and PhD students Tuhin Bhowmick, Soumitra Ghosh, Karuna Dixit, Debayan Dey, Varsha Ganesan, Udupi A Ramagopal.
The group has co-authored a paper on their findings which was published in Nature.com - an American website that publishes scientific journals.
A top official in the National Tuberculosis Institute confirmed that most drugs targeted the DNA gyrase and RNA polymerase components of the bacteria. "If the group has found a molecule that can target the Histone-like protein, then it is great news for us. Most TB cases in India go unreported. In about 12 percent of re-treatment cases, multi-drug resistant MTb has been found," he said on condition of anonymity.
Key to new drugs
While the finding is at the most basic and at the lowest end of the drug discovery process, it has the potential to be explored and developed into new classes of TB drugs in combination with other, existing drugs. "The molecule, which kills the bacteria by targeting the protein, has the potential to be tapped for introducing new drugs. We found that when the molecule is administered directly on the bacteria, it takes about a week's time to completely kill it," says Prof Nagaraja.
IISc's killer discovery to fight multiple drug resistant TB bacteria - Bangalore Mirror
