A groundbreaking study by researchers from Durham University, Jagiellonian University (Poland), and the John Innes Centre has shed new light on DNA gyrase, a critical enzyme found in bacteria and an essential target for antibiotics. The findings, published in Proceedings of the National Academy of Sciences, provide an unprecedented look at the enzyme’s mechanism, offering hope for the development of new antibiotic treatments against drug-resistant bacteria.
DNA gyrase operates as a molecular machine, intricately twisting and stabilizing bacterial DNA. This supercoiling process, akin to twisting an elastic band until it tightens, ensures that the bacterial DNA remains compact and functional. Unlike an elastic band, which untwists when released, DNA gyrase keeps the DNA in its coiled state by wrapping it into a ‘figure-of-eight’ loop. The enzyme then precisely cuts the DNA strands, passes them through each other, and reseals them. This delicate balance is essential, as leaving the DNA broken would be fatal for the bacteria.
Antibiotics such as fluoroquinolones exploit this process by preventing the resealing of DNA strands, thereby killing bacterial cells. However, the growing resistance to these antibiotics highlights the urgent need for a deeper understanding of gyrase’s function.
To address this, researchers employed advanced cryo-electron microscopy to capture high-resolution images of DNA gyrase in action. These snapshots revealed how the enzyme uses extended protein arms to manipulate DNA into its characteristic figure-of-eight structure. This new perspective challenges long-standing views of gyrase’s operation, offering fresh insights into its complex mechanics.
The study’s co-author, Professor Jonathan Heddle from Durham University, emphasized the significance of these findings, noting that they revealed unexpected details about the enzyme’s structure and movement. “The results suggested that the positions and sequence of the enzyme’s moving parts during supercoiling were not as previously understood, potentially influencing the design of new inhibitors,” he explained.
By unveiling the enzyme’s intricately coordinated mechanism, the study not only enhances our understanding of bacterial biology but also opens the door to next-generation antibiotics. These new drugs could be designed to target gyrase more effectively, circumventing existing resistance mechanisms.
Future research will aim to build on this discovery by capturing additional snapshots of gyrase in various stages of its operation. These images could eventually create a molecular “movie” of the enzyme’s activity, offering even greater insights into its function and vulnerabilities. Such detailed knowledge could accelerate the development of more precise and potent antibiotics to combat bacterial infections.
References:
Heddle, Jonathan, et al. "Structural Basis of Chiral Wrap and T-Segment Capture by Escherichia coli DNA Gyrase." Proceedings of the National Academy of Sciences, November 25, 2024. Accessed November 29, 2024. https://www.pnas.org/doi/10.1073/pnas.2407398121.
Phys.org. "Mechanism in Bacterial DNA Enzyme Opens Pathways for Antibiotic Development." November 25, 2024. Accessed November 29, 2024. https://phys.org/news/2024-11-mechanism-bacterial-dna-enzyme-pathways.html.
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