Researchers from Durham University (USA), Jagiellonian University (Poland), and the John Innes Centre (UK) have made significant progress in understanding DNA gyrase, a vital bacterial enzyme and key antibiotic target, paving the way for new antibiotic development.
This enzyme, found in bacteria but absent in humans, plays a crucial role in the supercoiling of DNA, a process essential for bacterial survival. Using high-resolution cryoelectron microscopy, the team revealed unprecedented details of gyrase's action on DNA, potentially opening doors for new therapies against resistant bacteria.
DNA gyrase functions like a small molecular machine that carefully twists and stabilizes bacterial DNA. This twisting, known as supercoiling, resembles winding a rubber band: as it twists, it coils tighter. Unlike a rubber band that would unwind if released, gyrase stabilizes the twisted form of DNA, making it functional for bacteria.
The enzyme wraps DNA in a figure-eight loop, then precisely breaks and passes strands over one another, sealing them afterward. This delicate process is critical; if the DNA remains broken, it would be lethal for the bacteria. Antibiotics like fluoroquinolones exploit this vulnerability by preventing the resealing of DNA, leading to bacterial cell death. However, resistance to these antibiotics is rising, highlighting the urgency of better understanding gyrase's function.
Utilizing cutting-edge cryoelectron microscopy, the team captured a snapshot of gyrase in action, revealing how it wraps DNA through extended protein arms to form the figure-eight shape. This finding updates the conventional view of gyrase's mechanism, which has been studied for decades. The images depict the enzyme as a highly coordinated multi-part system, with each piece moving in a precise sequence to achieve DNA supercoiling.
Reflecting on the study's findings published in the Proceedings of the National Academy of Sciences (PNAS), co-author Professor Jonathan Heddle from Durham University stated, 'The results suggested that the exact position and order of the enzyme's complex moving parts during the supercoiling process were not as we previously thought, which could impact how we design new inhibitors.'
This discovery not only enhances our understanding of bacterial biology but also promises new antibiotics designed to block gyrase more specifically, circumventing existing resistance mechanisms. With this high-resolution structure as a guide, researchers aim to capture additional snapshots of the enzyme at various stages, constructing a molecular movie of how gyrase operates. This detailed approach could aid in developing next-generation antibiotics that are more precise and effective against bacterial infections.