New drugs hope for dangerous yeast infections

Imperial research paves the way for new medicines that combat drug-resistant and deadly strains of fungal infections - News release

Imperial College London News Release

Under STRICT EMBARGO until
20.00 London time / 15.00 Eastern Daylight Time
Monday 5 September 2011

Researchers are a step closer towards creating a new class of medicines and vaccines to combat drug-resistant and deadly strains of fungal infections, following a new study published today in Proceedings of the National Academy of Sciences.

Yeast infections are the fourth most common cause of infection acquired by people in hospitals, although in healthy people they are most usually associated with vaginal or oral yeast infections known as thrush. In extreme cases in vulnerable patients, such yeasts can circulate in the bloodstream and spread throughout the body, causing systemic candidiasis. This is life-threatening in around half of patients when the infection spreads in this way.

Researchers from Imperial College London have now found out how yeast cells identify and attach to human tissue in order to colonise it and cause an infection. They have identified the key features in this process and now plan to create and test prototype drug-like molecules that interfere with the yeast and prevent the infection from taking hold.

There are already treatments that are effective at suppressing yeast infections and eliminating them from medical equipment, but microorganisms are constantly evolving to outsmart existing drugs and many strains of yeast have already become completely resistant to antifungal treatments. Scientists are seeking new ways to effectively kill them or prevent infection.

"Most healthy women will have thrush or other mild yeast infection at some point in their lives, but what is less well known is that yeasts can be lethal, and a major health concern for vulnerable hospital patients," said Dr Paula Salgado from the Department of Life Sciences at Imperial College London, one of the main investigators who carried out the research. "What I find most concerning is the fact that we don't seem to have an effective way to control the most severe cases of these infections. Our work allows us to understand the details involved and provide vital clues to develop new drugs and clinical applications."

Lead author of the research, Dr Ernesto Cota, and his colleagues from the Department of Life Sciences and the Centre for Structural Biology used data from high field magnets in Imperial's state-of-the-art Nuclear Magnetic Resonance (NMR) Centre as well as large x-ray research facilities across Europe to study a protein called Als adhesin on the surface of the yeast Candida albicans, in order to explore the role it plays in helping the yeast recognise human tissues.

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To help visualise the fine details of the recognition mechanism, they probed the structure of this fungal protein attached to a complementary human cell molecule using powerful x-rays at the UK’s national synchrotron facility, Diamond Light Source, in Oxfordshire. This allowed the researchers to fully identify which tiny part of Als adhesin attaches the yeast cell to human tissues and the exact features of that interaction.

"We have shown the unique way that Candida albicans has evolved to recognise and latch on to a wide variety of human cells. Als adhesin proteins give the yeast an ability to thrive throughout the human body, which is what makes it such a dangerous infect ion," said Dr Cota. "We hope this new knowledge will allow us to create drug-like molecules that prevent the yeast cells from taking hold, by blocking this specific molecular mechanism."

The researchers say their findings pave the way for commercial vaccines and anti-fungal compounds that are effective against a wide range of infection-causing fungi. The next step is to test small, drug-like compounds in the laboratory to analyse whether they behave as expected. These could then be developed into the first stages of new treatments.

Microscope view of Candida albicans cells, kindly provided by Dennis Kunkel, Inc.

"This work is exciting because it shows the great amount of insight that can be gained through interdisciplinary collaborations", said another author, molecular microbiologist Dr Lois Hoyer from the University of Illinois at Urbana-Champaign, who first discovered and characterized the Als adhesins. "The new data transform this field of study and highlight the next set of questions that can be answered by combining the structural biology in Dr Cota's group with the cellular biological expertise in my laboratory."

The study was funded by the Biotechnology and Biological Sciences Research Council (BBSRC) in the UK and the National Institutes of Health (NIH) in the United States.

- ENDS -

For further information please contact:

Simon Levey
Research Media Officer
Imperial College London
Email: s.levey@imperial.ac.uk
Tel: +44(0)20 7594 6702
Out of hours duty press officer: +44(0)7803 886 248

Notes to editors:

1.  Journal reference: Salgado PS, Yan R, Taylor JD, Burchell L, Jones R, Hoyer LL, Matthews SJ, Simpson PJ and Cota E, "Structural basis for the broad specificity to host-cell ligands by the pathogenic fungus Candida albicans" is published in Proceedings of the National Academy of Sciences on 5 September 2011 and under STRICT EMBARGO until 20.00 London time / 15.00 US Eastern time Monday 5 September 2011.

Download a copy of this study using the following link: https://icseclzt.cc.ic.ac.uk/download.php?claimID=hfU2c28S4q2gVN2H&claimPasscode=pWFR86cWbm7cYCzq&fid=8054

2.  About Candida albicans

Candida albicans is the most common fungal pathogen in humans, living in the mouth and gut of 80 per cent of all people. Usually benign, it can cause severe problems for the young, the elderly and those with compromised immune systems, including people undergoing chemotherapy, surgery or organ transplantation.

3.  About Imperial College London

Consistently rated amongst the world's best universities, Imperial College London is a science-based institution with a reputation for excellence in teaching and research that attracts 14,000 students and 6,000 staff of the highest international quality. Innovative research at the College explores the interface between science, medicine, engineering and business, delivering practical solutions that improve quality of life and the environment - underpinned by a dynamic enterprise culture.

Since its foundation in 1907, Imperial's contributions to society have included the discovery of penicillin, the development of holography and the foundations of fibre optics. This commitment to the application of research for the benefit of all continues today, with current focuses including interdisciplinary collaborations to improve global health, tackle climate change, develop sustainable sources of energy and address security challenges.

In 2007, Imperial College London and Imperia l 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.

• Website: www.imperial.ac.uk
• Twitter: www.twitter.com/imperialspark
• Podcast: www.imperial.ac.uk/media/podcasts

4.  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 £445M, 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 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: http://www.bbsrc.ac.uk For more information about BBSRC strategically funded institutes see: http://www.bbsrc.ac.uk/institutes

5.  About Diamond Light Source

Diamond Light Source produces the extremely intense X-ray beams required for looking at the molecular interactions involved in a variety of biological processes. Advances in structural biology have accelerated greatly as a result of access to the synchrotron facilities that have been developed around the world in the past 25 years. Researchers in the UK are at the forefront of this work and Diamond Light Source provides cutting edge facilities for protein structure determination.

Diamond currently has five experimental stations dedicated to structural biology as well as the on-site Membrane Protein Laboratory, recently developed in partnership with Imperial College London and funded by the Wellcome Trust. Since Diamond opened in 2007, over 500 protein structures have been solved there including enzymes associated with hypertension, tuberculosis and HIV.

• Diamond Light Source is funded by the UK Government via the Science and Technology Facilities Council (STFC) and by the Wellcome Trust.
• For more information about Diamond visit http://www.diamond.ac.uk
• Diamond generates extremely intense pin-point beams of synchrotron light of exceptional quality ranging from X-rays, ultra-violet and infrared. For example Diamond’s X-rays are around 100 billion times brighter than a standard hospital X-ray machine.
• Many of our everyday commodities that we take for granted, from food manufacturing to cosmetics, from revolutionary drugs to surgical tools, from computers to mobile phones, have all been develop e d or improved using synchrotron light.