01:45pm Friday 22 September 2017

Discovery of trigger for bugs' defences could lead to new antibiotics

Bacteria react to stressful situations – such as running out of nutrients, coming under attack from antibiotics or encountering a host body’s immune system – with a range of defence mechanisms. These include constructing a resistant outer coat, growing defence structures on the surface or producing enzymes that break down the DNA of an attacker.

The new research shows that a protein called sigma54 holds a bacterium’s defences back until it encounters stress, at which point the protein rearranges its structure to trigger the defences into action. The range of defences that sigma54 controls is so broad that the scientists are moving quickly to learn how to block its action and disable some of the bacteria’s armour.

The findings of the study are published today (21 August 2015) in the journal Science by researchers at Imperial College London with collaborators at Peking University in China, Pennsylvania State University and University of Wisconsin-Madison, in the USA.

Scientists already knew of sigma54’s existence but in the new research, the team used the UK’s national synchrotron facility – Diamond Light Source, based in Oxfordshire – to explore sigma54’s structure and function in minute detail.

A cellular machine called RNA polymerase (RNAP) is essential for enabling bacteria to function. In the study, the team used the advanced capabilities at Diamond’s Membrane Protein Laboratory to see for the first time how sigma54 directs RNAP to sit on the bacterial DNA, where it is poised to build the bacteria’s defences.

The RNAP-sigma54 complex can only work when it is activated and the scientists have long been trying to find out how sigma54 keeps RNAP in check, at a molecular level. They hope that ultimately, understanding how RNAP is controlled could lead to new ways of disabling bacterial defence mechanisms, and to new compounds that can kill bacteria.

Lead author Professor Xiaodong Zhang, from the Centre for Structural Biology and Department of Medicine at Imperial College London, said: “Bacteria are increasingly developing resistance to antibiotics and with the rise of resistant strains of diseases like tuberculosis, we desperately need to find new ways of tackling this problem.

“The RNAP machine is absolutely essential for a bacterium to function and in our new research we have uncovered multiple strategies that sigma54 uses to silence it. If we can find ways to harness sigma54’s ability to control bacteria’s defences, we can potentially inhibit bacteria from functioning normally, or prevent them from defending themselves. We are in the early stages of this research but if we are ultimately successful, we could give medicine the upper hand again,” she added.

 

Co-author Professor Martin Buck, from the Department of Life Sciences at Imperial College London, said, “Many important bacteria, such as Salmonella and Klebsiella, rely on this mechanism to trigger their stress responses and defences, which makes the prospect of manipulating it all the more tantalising. The use of sigma-54 and RNAP together to control the defences appears to be a very ancient but sophisticated strategy to control gene expression.”

This research was funded by BBSRC over the last four years, and following the publication of these findings a grant has been awarded from the Medical Research Council (MRC) to explore controlling genes in pathogenic bacteria, including Salmonella and Klebsiella.

The structure of the protein was determined by experiments at Diamond Light Source, where Imperial jointly runs the Membrane Protein Laboratory in partnership with Diamond. The cutting-edge laboratory is a research and training facility for scientists interested in solving the 3D structures of membrane proteins by X-ray crystallography.

The majority of the work was funded by the Biotechnology and Biological Sciences Research Council, with further support from the Chinese National Science Foundation, the China Scholarship Council and the National Institutes of Health.

ENDS

 

Notes to editors

 

Structures of the RNA polymerase-s54 reveal new and conserved regulatory strategies” is published in Science on Friday 21 August 2015 (under strict embargo for 19.00 UK time, Thursday 20 August 2015).

 

Authors: Yun Yang, Vidya C. Darbari, Nan Zhang, Duo Lu, Robert Glyde, Yiping Wang, Jared Winkelman, Richard L. Gourse, Katsuhiko S. Murakami, Martin Buck, Xiaodong Zhang.

 

About Diamond Light Source

 

Diamond Light Source, a joint venture between the UK Government and the Wellcome Trust, is located on the Harwell Science and Innovation Campus in Oxfordshire. By accelerating electrons to near light-speed, Diamond generates brilliant beams of light from infra-red to X-rays which are used for academic and industry research and development across a range of scientific disciplines including structural biology, physics, chemistry, materials science, engineering, earth and environmental sciences. For more information, please visit www.diamond.ac.uk

 

About Imperial College London

 

Imperial College London is one of the world’s leading universities. The College’s 14,000 students and 7,500 staff are expanding the frontiers of knowledge in science, medicine, engineering and business, and translating their discoveries into benefits for society.

 

Founded in 1907, Imperial builds on a distinguished past – having pioneered penicillin, holography and fibre optics – to shape the future. Imperial researchers work across disciplines to improve global health, tackle climate change, develop sustainable energy technology and address security challenges. This blend of academic excellence and its real-world application feeds into Imperial’s exceptional learning environment, where students participate in research to push the limits of their degrees.

 

Imperial nurtures a dynamic enterprise culture, where collaborations with industrial, healthcare and international partners are the norm. In 2007, Imperial College London and Imperial College Healthcare NHS Trust formed the UK’s first Academic Health Science Centre. This unique partnership aims to improve the quality of life of patients and populations by taking new discoveries and translating them into new therapies as quickly as possible.

 

Imperial has nine London campuses, including its White City Campus: a 25 acre research and innovation centre in west London. At White City, researchers, businesses and higher education partners are co-locating to create value from ideas on a global scale.

 

About BBSRC

 

BBSRC invests in world-class bioscience research and training on behalf of the UK public. Our aim is to further scientific knowledge, to promote economic growth, wealth and job creation and to improve quality of life in the UK and beyond.

 

Funded by Government, and with an annual budget of around £509M in 2014-2015 (£459M on research and capital grants and £50.5M for training and fellowships), we support research and training in universities and strategically funded institutes. BBSRC research and the people we fund are helping society to meet major challenges, including food security, green energy and supporting people to have healthier, longer lives. Our investments underpin important UK economic sectors, such as farming, food, industrial biotechnology and pharmaceuticals.

 

For more information about BBSRC, our science and our impact see: www.bbsrc.ac.uk.
For more information about BBSRC strategically funded institutes see: www.bbsrc.ac.uk/institutes.

 

External contact

Laura Gallagher, Research Media Relations Manager, Imperial College London


+44 20 7594 8432

 

Contact

 

BBSRC Media Office

 


+44 1793 414694


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