Using high-resolution cryo-electron microscopy (cryo-em), researchers from Durham University, Jagiellonian University, and the John Innes Centre uncovered unprecedented detail of gyrase’s action on DNA. The research could aid in the development of next-generation antibiotics that are more precise and effective in stopping bacterial infections.
Their findings are published in Proceedings of the National Academy of Sciences (PNAS) in an article titled “Structural basis of chiral wrap and T-segment capture by Escherichia coli DNA gyrase.”
DNA gyrase is a bacterial enzyme that introduces negative supercoils into DNA, which helps regulate DNA topology. It is present in bacteria but absent in humans and plays a crucial role in supercoiling DNA, a necessary process for bacterial survival.
The enzyme wraps DNA in a “figure-of-eight” loop, then precisely breaks and passes strands through each other, resealing them afterward. This is a delicate process—if the DNA remained broken, it would be lethal to the bacteria.
Antibiotics such as fluoroquinolones exploit this vulnerability by preventing the DNA resealing, which kills the bacterial cell. However, resistance to these antibiotics is growing, so a deeper understanding of how gyrase functions is urgently needed.
Cryo-em allowed the team to capture a snapshot of gyrase at work, revealing how it wraps DNA through outstretched protein arms to form the figure-of-eight shape.
This finding updates the conventional view of gyrase’s mechanism, which has been studied for decades. The images show 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 findings, co-author Jonathan Heddle, PhD, a professor at Durham University said: “The results suggested the exact position and the order of the complex moving parts of the enzyme during when the supercoiling process occurs were not quite as we previously thought, and this could impact how we design new inhibitors.”
This discovery not only advances our knowledge of bacterial biology but also holds promise for new antibiotics designed to block gyrase in a more targeted way, bypassing existing resistance mechanisms.
