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New research could help in fight against antibiotic resistance

New research has uncovered the structure of components responsible for transferring DNA from one bacteria to another and spreading antibiotic resistance

Transferring DNA from one bacteria to another enables bacteria to evolve and – critically – to spread antibiotic resistance genes between bacteria. New research from the Institute of Structural and Molecular Biology (ISMB) at Birkbeck, University of London and UCL has uncovered for the first time the structure of the components responsible for this process. The findings were published in the journal Cell.

Relaxomes are responsible for processing DNA before it is bound to the structure which transports it across the cell membrane and into a new cell. Relaxomes are made up of 3-4 components, the largest of which is relaxase, a protein responsible for attaching covalently to the DNA strand to be transferred and unwinding it, enabling that DNA strand to then be passed between cells.

In collaboration with the group of Professor Zechner (University of Graz), the ISMB team looked specifically at a relaxase known as Tral, which has four domains within it. Previous studies have uncovered details of parts of the protein, but this study was the first to uncover the structure of the full length of the protein, enabling understanding of how different parts cooperate and how it carries out its function.

Using highly sophisticated cryo-electron microscopy imaging techniques, the ISMB team discovered that Tral binds the single strand DNA along its entire length, rather than at one single domain. Moreover, two domain subparts appear to ‘clamp’ the DNA in place completely (and uniquely) surrounding it, but in order to do this they need to open, as if on hinges, to give the DNA access to the binding site.

Tral is known to be very processive – meaning that it is able to catalyse many consecutive reactions without releasing the bound DNA. As a result, it facilitates the very quick transfer of DNA – an entire bacterial genome can be then passed between cells within 1.5 hours. The team now believe that this processivity is likely due to the unique way in which the DNA is enclosed by the protein at certain points, and the fact that the DNA is bound along the length of the protein, providing a large binding site.

The findings are important as understanding more about the process by which bacteria transfer genetic material will enable scientists to develop new approaches to halting this process, and stopping antibiotic resistant genes from spreading.

Professor Gabriel Waksman, who led the research together with Dr. Giulia Zanetti (ISMB), said: “Relaxases have been much studied for many years, but this is the first time that the structure of the full length has been revealed. Because they drive the spread of antibiotic resistance genes among bacterial populations, relaxases are prime targets for new drugs. However, the lack of structural information on how its various domains cooperate in function has been a major obstacle in developing new drugs. With the structure reported here, renewed efforts in designing means to inhibit the process of gene transfer can now proceed.”

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