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Scientists are making progress in their quest to find an improved antibiotic for a strain of meningitis that results in over half a million deaths a year worldwide. The fungal disease Cryptococcal Meningitis is especially rife in AIDS patients and there are fears that if new drugs cannot be found, it could become untreatable. The results are published in one of the most respected journals in the field of membrane biology - Biochimica et Biophysica Acta – Biomembranes. Further experiments will be carried out at STFC’s ISIS neutron source this week (scheduled for 4 and 5 April 2011).

Cryptococcal Meningitis is diagnosed in nearly a million people a year worldwide, mainly in AIDS patients but also in others with defects in their cell mediated-immunity. More than 600,000 of these cases lead to fatalities. Currently, there is no vaccine for Cryptococcal Meningitis. Unlike most other strains of the disease, it is not passed from person to person, but is actually acquired from the environment, possibly by exposure to birds. The disease is most prominent in Sub-Saharan Africa but is also known to be on the increase in areas such as Thailand and India.

With funding from the Engineering and Physical Sciences Research Council, scientists from King’s College London have been using neutrons to look at the effects of the antibiotic Amphotericin which is currently used to treat Cryptococcal Meningitis. They hope this will help them devise new and more effective treatments, in particular for the disease-causing fungi that have developed a resistance to the drug.

"Such an approach, of course, requires that we fully understand how Amphotericin works, and unfortunately this is not the case", said David Barlow – the lead researcher from King’s College London.

"We do know that the drug has little effect on the cells in a human because these cells are surrounded by membranes containing cholesterol. We also know that the drug exerts its effects on fungi because their cells do not contain cholesterol, but instead have a related steroid, ergosterol. However it is quite unclear how this difference between human and fungal cell membranes matters to the workings of Amphotericin."

Research published in the journal Biochimica et Biophysica Acta – Biomembranes shows that Amphotericin can insert itself into cell membranes regardless of whether they contain cholesterol, ergosterol, or no sterol at all, and the resulting changes in the structure of the membrane seem to be the same for all three systems. This means the reason for the drug having less impact on human cells than fungal cells cannot purely be down to the fact that human cells contain cholesterol – other factors must be at play.

What seems more likely is that the drug interacts more rapidly with fungal cells than human cells, or that the structures it forms after inserting in to their membranes are different for the two types of cell.

"We're now going on to investigate the first of these possibilities, and during our next experiments at ISIS, we plan to look for differences in the speed with which the drug enters human and fungal cell membranes", said David Barlow. "The more information we can gather about how this complex system works, the more likely we are to be able to develop a new antibiotic that will be as effective as Amphotericin has been until recently".

In addition to Cryptococcal Meningitis, Amphotericin is also used to treat infections such as the tropical disease Visceral Leishmaniasis.

Notes to editors

The research involves using microscopic, bubble-like structures known as liposomes, prepared using different mixtures of fats, and either cholesterol or ergosterol, so that they mimic fungal or human cells. The structures of the membranes surrounding these liposomes are studied using a combination of advanced analytical techniques, looking also at how the membrane structures are changed in the presence of the antibiotic, Amphotericin. It is hoped the knowledge gained in these investigations will pave the way for others to design new and improved forms of antibiotic for use against Amphotericin-resistant fungal infections. The work is, however, currently in the very early stages.

The full scientific paper can be found here: http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T1T-526MS5F-4&_user=910841&_coverDate=02%2F18%2F2011&_rdoc=1&_fmt=high&_orig=gateway&_origin=gateway&_sort=d&_docanchor=&view=c&_acct=C000047841&_version=1&_urlVersion=0&_userid=910841&md5=eceb2155b818b24d4623066b1686b7b7&searchtype=a

More information on the rates and incidences of Cryptococcal Meningitis in AIDS patients can be found here: http://www.who.int/hiv/topics/mtct/HIV_Care_4-09.pdf

Images available:

Images of the ISIS facility used to carry out the work and a molecular model of Amphotericin are available. Please contact the Press Office for more details.

Contacts:

Lucy Stone

Press Officer

STFC Rutherford Appleton Laboratory

Email: lucy.stone@stfc.ac.uk

Tel: 01235 445627/07920 870125

ISIS Neutron Source

ISIS is a world-leading centre for research in physical and life sciences operated by the Science and Technology Facilities Council at the Rutherford Appleton Laboratory, Didcot, Oxfordshire, UK. http://www.isis.stfc.ac.uk/. ISIS produces beams of neutrons and muons that allow scientists to study materials at the atomic level using a suite of instruments, often described as a set of ‘super-microscopes’. ISIS supports an international community of over 2000 scientists who use neutrons and muons for research in physics, chemistry, materials science, geology, engineering and biology. It is the most productive research centre of its type in the world.

King's College London

King's College London is one of the top 25 universities in the world (2010 QS international world rankings), The Sunday Times 'University of the Year 2010/11' and the fourth oldest in England. A research-led university based in the heart of London, King's has nearly 23,500 students (of whom more than 9,000 are graduate students) from nearly 140 countries, and some 6,000 employees. King's is in the second phase of a £1 billion redevelopment programme which is transforming its estate.

King's has an outstanding reputation for providing world-class teaching and cutting-edge research. In the 2008 Research Assessment Exercise for British universities, 23 departments were ranked in the top quartile of British universities; over half of our academic staff work in departments that are in the top 10 per cent in the UK in their field and can thus be classed as world leading. The College is in the top seven UK universities for research earnings and has an overall annual income of nearly £450 million.

STFC

The Science and Technology Facilities Council is keeping the UK at the forefront of international science and tackling some of the most significant challenges facing society such as meeting our future energy needs, monitoring and understanding climate change, and global security.

The Council has a broad science portfolio and works with the academic and industrial communities to share its expertise in materials science, space and ground-based astronomy technologies, laser science, microelectronics, wafer scale manufacturing, particle and nuclear physics, alternative energy production, radio communications and radar

STFC operates or hosts world class experimental facilities including:

• in the UK; ISIS pulsed neutron source, the Central Laser Facility, HECToR (High-End Computing Terascale Resource) and LOFAR. STFC is also the majority shareholder in Diamond Light Source Ltd.

• overseas; the UK telescopes on La Palma, Hawaii and in Chile

It enables UK researchers to access leading international science facilities by funding membership of international bodies including European Laboratory for Particle Physics (CERN), the Institut Laue Langevin (ILL), European Synchrotron Radiation Facility (ESRF) and the European Southern Observatory (ESO).

STFC is one of seven publicly-funded research councils. It is an independent, non-departmental public body of the Department for Business, Innovation and Skills (DBIS).

http://www.stfc.ac.uk/

EPSRC

The Engineering and Physical Sciences research Council (EPSRC) is the UK’s main agency for funding research in engineering and physical sciences. EPSRC invests around £850m a year in research and postgraduate training, to help the nation handle the next generation of technological change.

The areas covered range from information technology to structural engineering, and mathematics to materials science. This research forms the basis for future economic development in the UK and improvements for everyone’s health, lifestyle and culture. EPSRC works alongside other Research Councils with responsibility for other areas of research. The Research Councils work collectively on issues of common concern via research Councils UK.