BBAU Makes a Significant Contribution in the Fight Against Tuberculosis: Researchers Develop a Realistic Virtual Model of ATP Synthase with the Help of a Supercomputer

Lucknow: Researchers from the Department of Biotechnology, Babasaheb Bhimrao Ambedkar University (BBAU), Dr. Yusuf Akhtar and Ms. Pragya Anand, have developed a virtual model of Mycobacterium tuberculosis ATP synthase in a realistic membrane environment, which may prove beneficial for understanding and improving the diagnosis and treatment of tuberculosis (TB). The study has been published in the Journal of Cellular Biochemistry (Wiley). By utilizing the national supercomputing infrastructure and competing at the global level, the BBAU research team successfully published its findings in an international journal, demonstrating the value of investing in India’s scientific capabilities. On this occasion, Vice-Chancellor Prof. Raj Kumar Mittal congratulated Dr. Yusuf Akhtar and Ms. Pragya Anand and described their achievement as a matter of pride for the University.

Dr. Yusuf Akhtar said during the discussion that while working on the PARAM Smriti Supercomputer, established under the National Supercomputing Mission, the team created a virtual model of Mycobacterium tuberculosis ATP synthase in a realistic membrane environment. The model consists of approximately 400,000 atoms, including the protein complex, the surrounding lipid bilayer, bedaquiline bound at its target site, and thousands of water molecules. The study revealed that bedaquiline does not remain fixed at a single position. While it remains firmly attached to its target site, it gradually shifts its orientation over time. This dynamic interaction is shaped not only by the protein itself but also by the surrounding membrane lipids and water molecules. This behavior helps explain how the drug disrupts the overall functioning of ATP synthase rather than merely blocking a single contact point. The study also shed new light on the proton pathways that drive the rotary motion of the molecular motor. Understanding their structure and behavior provides important clues for developing next-generation drugs capable of interfering more effectively with bacterial energy production while reducing the likelihood of resistance.

The research highlighted the active role of the bacterial membrane, which is often treated as a passive background in drug-interaction studies. Instead, the membrane emerged as a direct participant influencing both ATP synthase function and drug interactions. The team intends to investigate this membrane-associated role further, which could provide an even clearer molecular picture of the target. The significance of the study extends beyond a single drug. As TB treatment continues to evolve, the World Health Organization now recommends combination therapies of two to six months for drug-resistant TB, including several newer drugs such as bedaquiline. Future medicines must meet three critical requirements: they must remain effective against resistant bacteria, be safe for patients, and leave bacteria with fewer opportunities to escape treatment. By studying drug-target interactions at the atomic level in a realistic biological environment rather than in isolated proteins removed from their membrane context, this research offers a molecular blueprint for designing drugs capable of fulfilling all three requirements.

Tuberculosis remains one of the most devastating infectious diseases in human history. In 2024, approximately 10.7 million people worldwide developed TB, and about 1.23 million died from the disease, with more than one in four cases occurring in India alone. Poverty, overcrowding, malnutrition, delayed diagnosis, and incomplete treatment contribute to its spread, while cases of drug-resistant TB are increasing rapidly, making treatment more difficult and expensive. The causative bacterium, Mycobacterium tuberculosis, further complicates this challenge because it can slow its metabolism to an almost dormant state, rendering conventional antibiotics ineffective, while continuously mutating and finding ways to survive even in the presence of new drugs.

In 2012, bedaquiline was approved as a treatment for TB, representing the first genuinely new anti-TB drug in nearly fifty years. Unlike older antibiotics that target the bacterial cell wall or protein synthesis, bedaquiline attacks something even more fundamental, the bacterium’s ability to generate energy. Every living cell depends on adenosine triphosphate (ATP) to power its biological processes. ATP is produced by a remarkable molecular motor known as ATP synthase, located within the cell membrane and driven by the flow of protons like a turbine. Bedaquiline disrupts this motor in Mycobacterium tuberculosis, depriving the bacterium of the energy required for survival. While this strategy proved highly effective, it was not a permanent solution. Over time, resistance began to emerge, and concerns regarding the drug’s safety persisted. To unlock the full potential of bedaquiline, scientists needed to understand precisely how the drug interacts with ATP synthase at the atomic level and why these interactions sometimes fail.

ATP synthase is not a static structure but a continuously rotating machine embedded within a fluid membrane. The membrane itself determines how the machine operates, how drugs bind to it, and how resistance develops. To understand this dynamic behavior, researchers employ a powerful computational technique known as molecular dynamics simulation, in which supercomputers reconstruct every atom of a protein, its surrounding membrane, and water molecules, and simulate how these components move and interact over time. In this context, the research conducted by the BBAU team provides a detailed atomic-level account of the interaction between a crucial drug and the bacterial energy-production machinery. It represents the kind of fundamental science that enables the rational design of better medicines in the future.

Faculty members, research scholars, and students of the Department also congratulated the research team on this remarkable achievement.

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