Features

Seeing the interaction between antibiotics and the bugs they are designed to attack in three dimensions could help combat drug-resistant bacteria.

A team from Oxford University and Dundee University recently used the Diamond Light Source and ESRF to solve the 3D structure of the penicillin binding protein PBP3 from the bacterium Pseudomonas aeruginosa.

A report of the research is published in the Journal of Molecular Biology.

P. aeruginosa poses a particular risk to burns victims or people with a compromised immune system, for instance chemotherapy patients or people with HIV, and is resistant to most common antibiotics. The flexibility of penicillin binding proteins, such as PBP3, is key to how bacteria develop a resistance to drugs, mutating these proteins so that antibiotics can no longer ‘lock on’ to their intended targets.

By creating an accurate 3D picture of how the antibiotic binds to the protein PBP3, using X-rays produced at Diamond, the team now hope that it will be possible to develop new drugs to attack and destroy this tough bacterium.

Jingshan Ren, a member of the Oxford team, told us: 'The crystal structures of PBP3 and its complexes with antibiotics reveal how these drugs attack the bacteria in atomic resolution and provide a platform for developing new antibiotics to combat resistance using structure based drug design.'

The team included researchers from Oxford's Division of Structural Biology. 

The malaria parasite emerges and develops in synch with the bodyclock of its human host.

A study by scientists at Oxford and Edinburgh universities, published in Proceedings of the Royal Society B and covered by BBC News online and TIME has shown that the parasite suffers significant penalties if it doesn’t match its own bodyclock to the day-night pattern of its host. That is, it effectively suffers jetlag.

OxSciBlog asked co-author Dr Harriet McWatters of Oxford’s Department of Plant Sciences about the research and its implications for fighting disease.

OxSciBlog: What made you think that the malaria parasite might be able to tell the time?
Harriet McWatters: The symptoms of malaria (fever, chills) occur at regular intervals and usually at the same time of day. This is caused by the parasites emerging at the same time from red blood cells. This interval is always a multiple of 24 hours (48 or 72 hours in species that infect humans, and 24 hours in the rodent malaria we used in our study).

In order for the individual parasites to co-ordinate themselves so precisely, both with each other and the time of day, a clock must be involved.

OSB: How did you test your theory and what did you discover?
HM: We reasoned that parasites would do better when they were in synchrony with their hosts and did a very simple experiment with two separated groups of mice.

The first group was kept in a room lit between at 7am and 7 pm, the second in a room lit from 7pm to 7am. We created a mismatch between the internal clocks of the mouse and the parasite by initiating new infections in both groups in the morning, ie at lights on in room 1 and lights off in room 2.

We then watched the infections develop, counting the number of parasites in each group at regular intervals. Only half as many parasites were produced when there was a mismatch with the host’s bodyclock, or circadian rhythms.

This is very bad indeed for the parasites, as it substantially reduces their chance both of survival and of the possibility of transmission to a mosquito.

OSB: Why do the parasites emerge in the evening rather than at other times of day or night?
HM: We wanted to show that timing matters to the parasite. Clearly it does. We don’t yet know for certain why parasites choose to emerge in the evening but we have a few theories. In particular, we want to know why timing matters to the parasites: is it to evade the host’s immune system or to exploit a particular resource?

The parasites develop inside red blood cells, whose numbers peak in the evening. It could be that they time their emergence so as to make the most efficient use of a limited resource.

Alternatively, they could be trying to avoid components of the host’s immune response which are linked to the body’s circadian rhythm.

Or, it could be due to safety in numbers: if all the parasites emerge simultaneously then together they overwhelm the immune system and so increase their chance of infecting new red blood cells or a mosquito feeding on that blood.

OSB: How crucial is this timing to the survival and spread of the parasite?
HM: Our results suggest that it is very important indeed. We saw a 50% reduction in in-host replication rate. In addition, mismatched parasites produced only half the number of gametocytes. These are the reproductive stages which, when taken up by a mosquito, combine to form the next generation.

This means that the circadian mismatch is a double whammy for the parasites: it reduces by a half both the chance of survival in the host and the likelihood of transmission. This could well translate into a reduction in the ability to cause disease and for the disease to spread.

OSB: What are the implications for malaria treatments?
HM: We need to know why the parasite is so well co-ordinated with the host. It could be to shield the parasite from vulnerability to the immune system at a certain stage of its development. If so, this might make therapies more effective if they are given at a particular time of day.

OSB: Could your research improve the treatment of other infections?
HM: Although almost all organisms have bodyclocks that generate daily rhythms in behaviour and physiology, this is the first study showing the importance of circadian rhythms in host-parasite interactions.

We don’t yet know if this is a phenomenon specific to malaria or widespread among other protozoan parasites. If other parasites also need to synchronise their life cycle with their host’s daily rhythms, then developing means to weaken the parasite by disrupting this relationship could provide a new way of approaching treatments for these infections.

OSB: Are you planning further research in this area?
HM: Yes – we need to identify the mechanism by which the parasite knows what time it is. It could, for instance, be using host signals such as the rhythmic release of hormones like melatonin to tell the time or it could be responding directly to the daily pattern of light and dark. We would also like to know more about variability in timing, and whether the cell cycle can be speeded up or slowed down.

An innovative Oxford company has developed new solar cell technology that is manufactured from cheap, abundant, non-toxic and non-corrosive materials and can be scaled to any volume.

Harnessing the Sun’s energy, the solar cells are printed onto glass or other surfaces, are available in a range of colours and could be ideal for new buildings where solar cells are incorporated into glazing panels and walls.

Oxford Photovoltaics (Oxford PV), formed with the help of Oxford University Innovation, Oxford University’s technology transfer company, has combined earlier research on artificial photosynthetic electrochemical solar cells and semiconducting plastics to create manufacturable solid-state dye sensitized solar cells.

The device is a form of thin film solar technology, a relatively new development in solar energy generation.

Leading thin film technologies are currently hampered by the scarcity of minerals used. Other dye-sensitized solar cells are being held back by the volatile nature of liquid electrolytes.

Oxford PV’s technology replaces the liquid electrolyte with a solid organic semiconductor, enabling entire solar modules to be screen printed onto glass or other surfaces.

Green is the most efficient "semi-transparent" colour for producing electricity, although red and purple also work well.

The materials used are plentiful, environmentally benign and very low cost.

Oxford PV predicts that manufacturing costs of its product will be around 50% less than the current lowest-cost thin film technology and expects its new mechanism will eventually match the unsubsidised cost of electricity generated from fossil fuels.

The technology could revolutionise the incorporation of photovoltaic materials into windows and walls and other parts of buildings. CEO Kevin Arthur said: ‘This technology is a breakthrough in this area. We’re working closely with major companies in the sector to demonstrate that we can achieve their expectations on economic and product lifetime criteria.’

The technology was developed by Dr Henry Snaith, of Oxford University’s Department of Physics, who said, 'One of the great advantages is that we can process it over large areas very easily. You don’t have to worry about extensive sealing and encapsulation, which is an issue for the electrolyte dye cell.'

Problems related to pregnancy claim the lives of hundreds of thousands of women every year. Almost all of these deaths are in developing countries – the countries least able to provide effective medical care.

Pre-eclampsia is a serious problem of pregnancy and causes the deaths of more than 60,000 women annually, and many of their babies. There is huge potential to reduce these fatalities in developing nations.

The ambition of Dr Stephen Kennedy, head of Oxford’s Nuffield Department of Obstetrics & Gynaecology, is to help achieve this by educating health professionals globally on all aspects of maternal health. His vision is being backed by The John D & Catherine T MacArthur Foundation, which is funding the development of web-based materials to improve pre-eclampsia care.

Pre-eclampsia is characterised by high blood pressure and protein in the urine and, if left untreated, can cause strokes, kidney and liver damage, and death. The condition usually develops after the 20th week of pregnancy with early delivery of the baby the usual treatment. It is much rarer in developed countries where the drug magnesium sulphate, the most effective treatment, has been available at low cost for 20 years.

There are three obstacles preventing improvements in pre-eclampsia care in poorer countries: the absence of national guidelines based on effective treatments, too few specialists, and scarce supplies of magnesium sulphate, also known as Epsom salts.

To tackle the first of these problems, Oxford University is joining forces with eXact learning solutions, a provider of online distance learning material.

With the Nuffield Department of Obstetrics & Gynaecology and the Oxford Maternal & Perinatal Health Institute the company is developing a web-based training pilot for midwives, nurses and doctors. The material will be used initially in hospitals in India, Mexico and Nigeria, where pre-eclampsia is most common.

The initiative is being funded by The John D & Catherine T MacArthur Foundation which stepped in after a conference in 2007 hosted jointly by Oxford University and EngenderHealth. Delegates called for magnesium sulphate to be readily available in developing world hospitals together with training and protocols in its use.

The partners’ long-term objective is to offer the training course worldwide. Dr José Villar, who is leading Oxford University’s work with eXact learning solutions, said: ‘Treatment for pre-eclampsia should be equally available in developing countries and the developed world.

‘Our work with eXact learning solutions will make significant inroads into improving global healthcare for those suffering pre-eclampsia. The aim now is to win additional funding to develop this pilot initiative into a far larger programme of education and treatment.’

Bacteria have a canny way of protecting themselves from attack by toxic chemicals, aiding their survival and development. They have small channels in their cell wall, some of which can shut if there is no threat or open to help fight the toxins.

These tiny channels act as molecular ‘gatekeepers’. They control the flow of ions into and out of the cell and in that way safeguard bacteria, including the superbugs, E.coli, Salmonella and Legionella. If the channels could be kept open artificially, bacteria could be killed or their growth hindered.

Stuart Conway from Oxford University’s Department of Chemistry is part of a team studying the survival mechanisms of bacteria. The group’s latest research used synthetic chemicals to open and close the protective channels.

The new study, published in this week's PNAS, reveals that the channels work like molecular switches, sensing the presence of toxic chemicals. Some chemicals keep the channels shut but other chemicals can open them up, helping the bacteria to survive.

When a toxin is detected, the channels open, increasing the acidity, or pH, of the cell, which prevents damage. When the threat has passed, the channels close, allowing the cell to revert back to its normal pH.

Stuart, and colleagues from the University of Aberdeen and University of St Andrews, see the channels as targets for new antibiotic drugs. They hope further research will facilitate the development of alternative treatments to tackle bacteria that are resistant to existing antibiotics.

'We are very excited about applying our chemical tools to the study of fundamental biological problems, which may ultimately allow us to develop new leads for novel antibiotic drugs,' Stuart told us.

Dr Stuart Conway is based at Oxford University's Department of Chemistry.