One of the difficult and never-ending struggles of our time is Tuberculosis, a disease caused by the bacterium Mycobacterium tuberculosis (M.TB), which spreads through the air when infected individuals cough or sneeze. Researchers have even discovered traces of this "breath-draining killer" in mummies dating back 7000 years, unearthed from a Hungarian crypt in 2015. Even after ages of battling, its highly contagious nature and drug resistance make this tiny organism a global health challenge. Today, tuberculosis is ranked as the second most deadly infectious disease after COVID-19.
Researchers at the National Centre for Biological Sciences have made important structural analysis in a recent study, paving the way for new drugs. Their findings suggest a new method to combat tuberculosis by blocking a vital process essential for its survival.
Antibiotics are the first line of defence against bacterial infections. Rifampicin is one of the antibiotics commonly used to fight tuberculosis. It attacks a key player in this bacteria's transcription machinery, RNA Polymerase, an enzyme crucial for making proteins and keeping cells alive and functioning. When RNA polymerase and DNA interact, it copies the information from DNA onto RNA. RNA then travels to the cell’s protein-making factories where it guides the assembly of proteins. Rifampicin prevents this interaction between DNA and RNA polymerase, eventually killing the bacterium. However, the emergence of deadly Rifampicin-resistant bacteria is making the treatment challenging, seeking an urgent requirement of new medicines.
Dr. Sneha Bheemireddy, working at the Molecular Biophysics Unit, Indian Institute of Science, and with Prof. Sowdhamini at the National Centre for Biological Sciences, began searching for the Achilles’ heel that RNA Polymerase might have. They conducted molecular dynamics simulations and perturbation response scanning to study how RNA Polymerase interacts with RbpA, a helper molecule necessary for its function in M. TB. They discovered that the structure of RNA polymerase is formed of pivotal alpha subunits that fit together like a puzzle. The research team argued that disruption of this foundation could prevent the formation of RNA polymerase altogether.
The team then focused on finding drugs that could bind to the alpha subunits, hindering the assembly of the entire RNA Polymerase complex, similar to stealing the foundational blocks of the machine, causing it to fail and stopping the bacteria from making the proteins they need to survive.
“Targeting the alpha subunits of RNA polymerase in M.TB is a smart move compared to Rifampicin, which goes after the beta subunits. These alpha subunits are important for kicking off the transcription process. They are specific to this crucial task, making them better targets for drugs. And they are less likely to develop resistance. By focusing on alpha subunits, we aim to selectively disrupt transcription initiation, opening up exciting possibilities for fighting Tuberculosis, said Dr Bheemireddy
Using computational methods, they identified two promising drugs, Saikosaponin-F and Elbasvir, that can target the alpha subunits. Notably, Elbasvir is an FDA-approved drug for Hepatitis C, meaning it has already passed rigorous safety and efficacy tests, which could accelerate its repurposing for tuberculosis treatment. While the simulations and predictions are promising, further experimental studies are required to validate their effectiveness and safety.
"Long-distance or allosteric regulations are well-known in structural biology. Of late, there is a quest for allosteric drugs and this computational approach fits within this regime and could enable a fight against antimicrobial resistance", says Prof Sowdhamini.
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