̽��ֱ�� of Cambridge - antibiotic

Reducing the rise of antibiotic resistance

lw355 — Mon, 22 Nov 2021 12:00:01 +0000

Rising resistance to antibiotics is a worrying prospect, but a success story happening across the farms of the UK gives hope that something can be done.

Women in STEM: Dr Anna-Maria Pappa

sc604 — Thu, 05 Sep 2019 06:00:00 +0000

I strongly believe that through diversity comes creativity, comes progress. I qualified as an engineer in the Department of Chemical Engineering at Aristotle ̽��ֱ�� of Thessaloniki, Greece, and went on to earn a Master’s Degree in Nanoscience and Nanotechnology from the same university. My PhD is in Bioelectronics from École des Mines de Saint-Étienne in France, and a key moment for me was when I left home to study abroad. Leaving my comfort zone for something unknown was very difficult in the beginning, but proved to be an invaluable experience. I met people from all over the world with different cultures and mind-sets, stretched my mind and expanded my horizons.

I find it very difficult to be around like-minded people; I always look for those with different views. I’m working on a drug discovery platform using bioelectronics, and my work sets out to improve and accelerate drug discovery by providing novel technological solutions for drug screening and disease management. My research focuses on the application of a new class of electronic materials and devices that could replace the in-vitro drug screening assays currently used in medical diagnoses with electronic arrays similar to the electronic chips found in mobile phones. These could quickly assess the health of our cells, outside of our bodies.

As an engineer, creating solutions to important yet unresolved issues for healthcare is what truly motivates me. I hope my research will lead to a product that will impact healthcare. ̽��ֱ��convergence of new technologies with life sciences will revolutionise both diagnosis and therapy. I imagine a healthcare system where the standard one-size-fits-all approach shifts to a more personalised and tailored model.

My most interesting project is one that is working to tackle the global challenge of antimicrobial resistance from a technological standpoint. We are developing biomimetic bacterial membranes on top of our devices and screening newly synthesised antibiotics. Investigating drug-bacterial membrane interactions allows us to directly test the efficacy of known drugs on bacterial resistant strains, as well as allowing us to better understand the action of novel drugs on the membrane properties, and ultimately aid the design and synthesis of target-specific antibiotics.

I joined Cambridge as a postdoctoral researcher in 2017. My daily routine involves some lab work in the Department of Chemical Engineering and Biotechnology, a lot of reading and writing, and some project management. I spend time in the Maxwell Centre too, where I participate in an entrepreneurship program called Impulse, exploring all the aspects of technology transfer.

Being part of a ̽��ֱ�� where some of the world's most brilliant scientists studied and worked is invaluable. Cambridge combines a historic and traditional atmosphere with cutting edge technological and scientific research in an open, multicultural society. ̽��ֱ��state-of-the-art facilities, and the openness in innovation and collaborations, along with great science, provide a unique combination that can only lead to excellence. I also travel frequently for conferences, as well as visiting other laboratories across Europe, the United States and Saudi Arabia. When you work in a multidisciplinary field it is essential to establish and keep good collaborations; since this is the only way to achieve the desirable outcome.

To be successful in a postdoctoral role requires management, teaching, networking, proposal writing and travelling. ̽��ֱ��amount of time you get to spend in the lab drops significantly compared to the PhD research period. This is in part due to the fact that you are more experienced, thus more efficient, and since you are more independent in research you need to be on top of things.

I think it’s absolutely vital, in every opportunity, for all of us to honour and promote girls and women in science. In October 2017 I was delighted to be awarded a L'Oréal-UNESCO For Women in Science Fellowship, an award that honours the contributions of women in science. For me, the award not only represents a scientific distinction but also gives me the unique opportunity, as an ambassador of science, to inspire and motivate young girls to follow the career they desire. Unfortunately, women still struggle when it comes to joining male-dominated fields, and even to establish themselves later at senior roles. We still face stereotypes and social restrictions, even if it is not as obvious today as it was in the past. This is in part due to the fact that still, the key senior roles are predominantly male-occupied, and so there is a lack of female role models as well as female mentality. This makes it harder for women to believe in themselves and achieve their goals.

A question I always ask during my outreach activities at schools is ‘do look like a scientist?’ ̽��ֱ��answer I get most times is ‘no’! I think this misperception of how professionals in STEMM look, or about what they actually do on a daily basis is what discourages girls early on to follow STEMM careers. This needs to change. On top of that, my advice to women would be to be open, never underestimate themselves and never be put off by stereotypes especially in male-dominated industries. There are excellent examples of highly successful women – leaders in their fields - who managed to excel despite the difficulties. Importantly, many of them successfully combined career and family.

Dr Anna-Maria Pappa is a postdoctoral researcher in the Department of Chemical Engineering and Biotechnology and holds the Oppenheimer Research Fellowship and Maudslay-Butler Research Fellowship from Pembroke College. Her research is focused on the global challenge of antimicrobial resistance.

Anna-Maria Pappa

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Women in STEM: Josie Gaynord

sc604 — Thu, 04 Jul 2019 06:36:50 +0000

My research sets out to develop new types of antibiotics. Antimicrobial resistance is a global concern at the moment which could threaten public health and food provision as bacteria can develop resistance quickly to common antibiotics. My research is looking at creating new antibiotics which combine old and new drugs with different mechanisms of actions to try and prevent resistance from developing.

As a chemist, I am constantly amazed by biology. Some of my research is looking into creating new drugs for blood-related diseases, and recently I was able to spend the day looking at blood cells through a microscope – this might not sound very interesting but being able to see it all with my own eyes was incredible and not something you’re able to do day-to-day as a chemist. I want to improve healthcare and this helps spur me on when nothing is working. I think it’s important for all scientists to keep in mind why we want to do our research, and why it is important. I hope my research will lead to at least one drug which is more effective, or has fewer side effects, that what is currently available to patients.

My work is laboratory-based - I spent the majority of my time synthesising biologically-relevant compounds. To test these, I visit groups or institutions that the Spring Group has collaborations with, including other departments, other universities and industrial pharmaceutical companies (all within Cambridge). I also have a collaborative research project with a group at the Technical ̽��ֱ�� of Denmark, so have travelled there in the past. It’s always a great moment when I finally manage to make a compound that I’ve been working on for months. After trying again and again, it’s such a good feeling when the hard work pays off.

I am lucky that I am surrounded by amazing, inspirational and nurturing women who are there to help me and prove that women can succeed in STEMM. Having mentors and strong female friendships within your field is very important.

While you should always be ambitious and work towards your goals, remember to give back. Do every sort of outreach, public speaking and wider-engagement event that you are offered, because one of the most important things is representation. Subconsciously, young girls will never believe that they can be successful if women in STEMM are not visible.

Josie Gaynord is a PhD candidate in the Department of Chemistry under the supervision of Professor David Spring. Her research looks at one of the biggest problems threatening global public health: antimicrobial resistance, or AMR.

Yes

Postgraduate Pioneers 2017 #1

ta385 — Tue, 17 Oct 2017 10:00:00 +0000

First in the series is Himansha Singh, a Pharmacologist from India whose research aims to help tackle antimicrobial resistance.

My research sets out to

Today, we can survive an organ transplant but then die because of a bacterial infection. ̽��ֱ��rise of antimicrobial resistance (AMR) and ‘superbugs’, along with the lack of antibiotic development in the last decades, is a major concern for global healthcare. Whilst there are several mechanisms responsible for AMR, our research group is examining multidrug efflux pumps or transporters that expel drugs rendering bacteria resistant to a broad range of antibiotics.

While we know some things about the architecture of bacteria, we don’t fully understand how they conduct transportation of antibiotics. If we could understand their operating system, we could develop compounds, which might help switching off the system and stop them from rejecting antibiotics. In particular, my project is looking into a very interesting E.coli ATP-binding cassette (ABC) transporter MsbA. We are working towards characterising how this protein uses energy to operate dynamic changes in its structure to facilitate drug transport.

My Motivation

During my master's degree, I worked with AstraZeneca and my neighbouring lab was working on transporters in drug development. Their work caught my attention. I also visited India that summer and my hometown, Gwalior, in Madhya Pradesh, was suffering a severe outbreak of tuberculosis and typhoid. These experiences exposed me to the seriousness of antibiotic resistance. Transporters play a huge role in this and after reading up on the topic, I looked for a relevant PhD project and was delighted to be accepted into Dr Hendrik W. van Veen's lab to work on various transporters, both in humans and bacteria.

Day-to-day

I am based in the Department of Pharmacology, which is in the city center – it’s a great location. I work in a team of ten and my average day in the lab is spent working on culturing liters of bacterial cells to extract MsbA and reconstitute it in artificial lipid membranes. I then test MsbA activity under different energy conditions and drugs, or test different inhibitors.

My best days

That has to be when we first noticed that the ATP dependent transporter MsbA could also work without ATP. ATP is an energy currency of cells and ABC transporters, such as MsbA, utilize it as their main source of power for drug transport. But we showed that MsbA is also dependent on another form of energy source, an electrochemical gradient. In fact, MsbA cannot function without the involvement of both of these power sources. That brought a paradigm shift in our understanding of translocation by MsbA, which may lead us to new ways to tackle bacteria.

I hope my work will lead to

Apart from being a multidrug transporter, MsbA is an essential membrane protein that transports phospholipids in E.coli to form its cell membrane; so inhibiting this pump is clinically important to develop or establish foundations for a new class of antibiotics against E.coli. We can only design inhibitors if we know the fundamental basis of their transport mechanism and I hope my PhD research will provide some insight into this. We believe that our findings will be of great interest to the wider scientific community.

It had to be Cambridge because

My supervisor, Dr. Hendrik W. van Veen has played a crucial role in developing my enthusiasm for scientific research. And Cambridge has provided a tight-knit, supportive and stimulating intellectual environment which has shaped my career and understanding of academia in really important ways. Other than benefiting from the world-class research facilities in my lab and department, I’ve been able to immerse myself in Cambridge’s rich culture and exciting critical atmosphere. ̽��ֱ��collegiate system also ensures a thriving social life and this paved the way for me to develop interests in various other disciplines over formal dinners and drinks in our college bars.

In 2017, Himansha Singh was one of twelve PhD students to win an award from the Cambridge Society for the Application of Research.

With our Postgraduate Open Day fast approaching (3 Nov), we introduce five PhD students who are already making waves at Cambridge.

I have benefited from world-class research facilities and immersed myself in Cambridge’s rich culture.

Himansha Singh

Himansha Singh, Dept of Pharmacology

Postgraduate Open Day

For more information about the ̽��ֱ��'s Postgraduate Open Day on 3rd November 2017 and to book to attend, please click here.

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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Massive projected increase in use of antimicrobials in animals could lead to widespread antimicrobial resistance in humans

sc604 — Thu, 28 Sep 2017 18:00:00 +0000

̽��ֱ��researchers, from ETH Zürich, Princeton, and the ̽��ֱ�� of Cambridge, conducted the first global assessment of different intervention policies that could help limit the projected increase of antimicrobial use in food production. Their results, reported in the journal Science, represent an alarming revision from already pessimistic estimates made in 2010, pushed up mostly by recent reports of high antimicrobial use in animals in China.

In modern animal farming, large quantities of antimicrobials are used for disease prevention and for growth promotion. “Worldwide, animals receive almost triple the amount of antibiotics that people do, although much of this use is not medically necessary, and many new strains of antibiotic-resistant infections are now common in people after originating in our livestock,” said co-author Emma Glennon, a Gates Scholar and PhD student at Cambridge’s Department of Veterinary Medicine. “As global demand for meat grows and agriculture continues to transition from extensive farming and smallholdings to more intensive practices, the use of antimicrobials in food production will increasingly threaten the efficacy of these life-saving drugs.”

Global policies based on a user fee and stricter regulation could help mitigate those ominous projections. “Under a user fee policy, the billions of dollars raised in revenues could be invested in the development of new antimicrobial compounds, or put towards improving farm hygiene around the world to reduce the need for antibiotics, in particular in low- and middle-income countries,” said Dr Thomas Van Boeckel from ETH Zurich, the study’s first author.

Compared to a business as usual scenario, a global regulation putting a cap of 50 mg of antimicrobials per kilogram of animal per year in OECD countries could reduce global consumption by 60% without affecting livestock-related economic development in low-income countries.

However, such a policy may be challenging to enforce in resource-limited settings. An alternative solution could be to impose a user fee of 50% of the current price on veterinary antimicrobials: this could reduce global consumption by 31% and generate yearly revenues of between US$ 1.7 and 4.6 billion.

An important limiting factor in performing this global assessment was accessing sufficient data on veterinary antimicrobial sales volumes and prices. ̽��ֱ��present study is based on publicly available data, limited to 37 countries. Representatives from the animal health industry were approach for this study but all declined to share information on antimicrobial sales or prices.

̽��ֱ��research was funded by the program for Adaptation to a Changing Environment, the ETH postdoctoral fellowship program and the European Research Council.

Reference:
Thomas P. Van Boeckel et al. ‘Reducing global antimicrobial use in food animals.’ Science (2017). DOI: 10.1126/science.aao1495

Adapted from at ETH Zurich press release.

̽��ֱ��amount of antimicrobials given to animals destined for human consumption is expected to rise by a staggering 52% and reach 200,000 tonnes by 2030 unless policies are implemented to limit their use, according to new research.

Worldwide, animals receive almost triple the amount of antibiotics that people do.

Emma Glennon

Marcelo Braga

Expresso Porco

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A whole host of options

cjb250 — Fri, 09 Oct 2015 08:30:04 +0000

Professor Lalita Ramakrishnan is, it’s fair to say, a world authority on the biology of TB. She studies the disease – one which most people will know of as a disease of the lungs – using what at first sight seems an unusual model: the zebrafish.

“What most people don’t realise is that about 40% of human TB occurs outside the lungs,” explains Ramakrishnan. “It can infect the brain, bone, heart, reproductive organs, skin, even the ear. In fact, TB infection is a basic biology question, and this is the same in zebrafish as it is in humans.”

TB is caused by Mycobacterium tuberculosis, which is generally transmitted from person to person through the air. It has been around since at least the Neolithic period, but its prevalence in 19th-century literature led it to be considered something of a ‘romantic’ disease. ̽��ֱ��truth is a long way from this portrayal. ̽��ֱ��disease can cause breathlessness, wasting and eventual death. And while treatments do exist, the drug regimen is one of the longest for any curable disease: a patient will typically need to take medication for six months.

Ramakrishnan is involved in a new trial due to start soon that might allow doctors to reduce the length of this treatment. She is cautiously optimistic that it can be reduced to four months; if successful, however, it may eventually lead to treatments more on a par with standard antibiotic treatments of a couple of weeks.

̽��ֱ��trial builds on work in zebrafish carried out by Ramakrishnan and colleagues at the ̽��ֱ�� of Washington, Seattle, before she moved to the Department of Medicine in Cambridge in September 2014. These small fish, which grow to the length of a little finger, helped her and collaborator Professor Paul Edelstein from the ̽��ֱ�� of Pennsylvania (currently on sabbatical in Cambridge) to make an important discovery that could explain why it takes a six-month course of antibiotics to rid the body of the disease (rather than seven to ten days that most infections take) and yet in the lab can easily be killed.

Within our bodies, we have a host of specialist immune cells that fight infection. One of these is the macrophage (Greek for ‘big eater’). This cell engulfs the TB bacterium and tries to break it down. This, together with powerful antibiotics, should make eliminating TB from the body a cinch. Ramakrishnan’s breakthrough was to show why this wasn’t the case: once inside the macrophages, TB switches on pumps, known as ‘efflux pumps’. Anything that we throw at it, it just pumps back out again.

“Once we’d identified the pumps, we started to look for drugs that are out there in the market and tested a few of them,” she explains. “We found that verapamil, an old drug, made the bacteria susceptible to two of the antibiotics we use to fight TB.”

̽��ֱ��trial of verapamil, which is commonly used to treat high blood pressure, is due to start soon at the National Institute for Research in Tuberculosis (NIRT) in Chennai, India.

Ramakrishnan is one of a number of brilliant minds working as part of a collaboration between the NIRT and the ̽��ֱ�� of Cambridge to apply the very latest in scientific thinking and technology to the problem of TB.

An expansion of this collaboration has now become possible through the recent award of a £2 million joint grant from the UK Medical Research Council (MRC) and the Department of Biotechnology (DBT) in India, which will enable the exchange of British and Indian researchers. For Professor Sharon Peacock, the UK lead on the proposal, this means an opportunity to train a new cohort of early-career researchers in an environment where they will have access to outstanding scientific facilities and training, at the same time as becoming familiar with the clinical face and consequences of TB for people in India.

“India is home to a large pool of talented young people with the potential to help fight back against this deadly disease,” says Peacock. “Developing a close collaboration between Cambridge and Chennai involving two-way traffic of scientists and ideas is an exciting opportunity to start to tap into this.”

There are few places more suitable for the proposed work than India. According to the World Health Organization, India is home to almost one in four of all worldwide cases of TB, with over two million newly diagnosed cases in 2014.

Not only that, but it is one of the countries that has seen an increase in the number of cases of drug resistance to TB – including ‘multi-drug’-resistant, and even more worrying, ‘extremely’ drug-resistant strains of TB against which none of our first- and second-line drug treatments work. In part, this increase reflects improved access to diagnostic services, but the situation highlights why new approaches to tackling the disease are urgently needed, says Professor Soumya Swaminathan, Director of NIRT and the India lead in the collaboration.

“So far, the treatment of TB has focused almost exclusively on using drugs to try to kill the bacteria directly, but there’s increasing evidence that there may be benefits to targeting the host. TB is very clever and it manipulates the host immune system to its own advantage, so if we could use drugs to help the immune system, then we may be able to make it more effective.”

This is the approach that Professors Ken Smith and Andres Floto from the Department of Medicine at Cambridge, also part of the collaboration, are taking. Smith is looking at the role that specialist immune cells known as T cells play in the persistence of multi-drug-resistant strains of TB. His group has evidence that around two thirds of the population have T cells which have a tendency to become ‘exhausted’ when activated.

“It might be that exhausted T cells can’t fight multi-drug-resistant TB effectively, in which case we need to find a way to overcome this exhaustion and spur the T cells on to rid the body of the disease,” says Smith.

For Floto, the key may lie in the role played by the macrophages and their otherwise voracious appetites. As their Greek name suggests, macrophages ‘eat’ unwanted material (surprisingly similar in action to Pac-Man), effectively chewing it up, breaking it down and spitting it out again.

This process, known as autophagy (‘self-eating’), is a repair mechanism for clearing damaged bits of cells and recycling them for future use, but also works as a defence mechanism against some invading bacteria. So why, when it engulfs TB, does the bacterium manage to avoid being digested?

“Autophagy is partially inhibited by TB itself, but we found that if you overstimulate this mechanism – like flooring the accelerator of a car – you can overcome the bacteria,” explains Floto. “Clearly this will be applicable to normal TB, but we already have drugs that are effective against this. We want to know if this would work against multi-drug-resistant strains.”

Floto and colleagues already have a list of potential drugs that can stimulate autophagy, drugs that have already been licensed and are in use to treat other conditions, such as carbamazepine, which is used to treat epileptic seizures. These drugs are safe to use: the question is, will they work against TB?

“We’ve already shown that carbamazepine stimulates autophagy in cells to kill TB – even multi-drug-resistant TB. We now want to refine it and test it in mice and in fish, alongside a shortlist of around 30 other potential drugs,” he adds.

TB evolves through ‘polymorphisms’ – spontaneous changes in the letters of its DNA to create variants. Because the drug regimen to fight the disease lasts so long, many patients do not take the full course of their medicines. If the TB is allowed to relapse, it can evolve drug resistance.

These patterns of resistance can be detected using genome sequencing – reading the DNA of the bacteria. Peacock believes this technique may be able to help doctors more easily diagnose drug resistance in patients.

“TB is very slow to grow in the laboratory, which means that testing an organism to confirm which antibiotics it is susceptible or resistant to can take several weeks, especially in the case of more resistant strains,” she says. “There is increasing evidence that antibiotic resistance can be predicted from the genome sequence of the organism, and we want to establish and evaluate this technology in India, where it is needed.”

This sequencing data could also then help inform the search for new drugs, explains Professor Sir Tom Blundell from the Department of Biochemistry. He is no stranger to TB: his grandfather died from the disease shortly after the war – though, as Blundell points out, this strain of TB is far less common now, as the organism has evolved in different communities throughout the world.

“We can take the polymorphisms and ask questions such as ‘What does this mean for the use of current drugs?’” says Blundell. “ ̽��ֱ��nature of the polymorphisms in the TB genome sequence of an infected individual can give us information on where that person was infected and what are the drugs that might be most effective. We can then begin to look at new targets for particular polymorphisms.”

Blundell plans to take the information gathered through the Chennai partnership and feed it into his drug discovery work. He takes a structural approach to solving the problem: look at the shape of the polymorphism and its protein products and try to find small molecules that can attach to and manipulate them. In essence, it’s akin to picking a lock by analysing the shape of its mechanism and trying to identify a key that could turn it, thus opening the door.

Yet even if the Chennai venture is successful, and research from the partnership leads to a revolution in how we understand and treat TB, the team recognise that this is unlikely to be enough to eradicate the disease for good.

“TB is as much a public health issue as one of infectious diseases,” says Ramakrishnan, pointing to Europe, where even before the introduction of antibiotics, the disease was already on the decline. “We need better nutrition, better air, less smoking, reductions in diabetes.”

Swaminathan agrees. “TB is very much associated with poverty and all the risk factors that go with it,” she says. “When people are living in very crowded conditions, when they’re malnourished, TB is going to continue to spread. This is happening in the slums of Mumbai, for example, where we’re seeing a mini-epidemic of multi-drug-resistant TB. Unless we see a rapid improvement in the living standards of people we’re not going to see a very major effect. There’s only so much we can do biomedically.”

Inset image: Macrophage engulfing Tuberculosis pathogen (ZEISS Microscopy).

Almost one in four of the world’s cases of tuberculosis (TB) are in India and the disease is constantly adapting itself to outwit our medicines. Could the answer lie in targeting not the bacteria but its host, the patient?

What most people don’t realise is that about 40% of human TB occurs outside the lungs ... It can infect the brain, bone, heart, reproductive organs, skin, even the ear

Lalita Ramakrishnan

Calcutta Rescue

Picture to educate people in villages that have no medical service about the spread of TB

̽��ֱ��Next Generation

If there’s one thing on the side of science v. TB, it’s the wealth of talent available in India.

Professor Sir Tom Blundell is quick to praise the Indian postdocs that come to work in his lab. “They tend to be naturally very inquisitive and interactive, with very enquiring minds,” he says.

This is something with which Professor Ashok Venkitaraman, Director of the Medical Research Council (MRC) Cancer Unit at Cambridge, wholeheartedly agrees. He has helped establish the Center for Chemical Biology and Therapeutics (CCBT) in Bangalore in part, he says, because “the number of really bright, well-trained young scientists in India is huge. ̽��ֱ��level of enthusiasm and commitment is something I find quite exceptional.”

̽��ֱ��CCBT is an inter-institutional centre that links the Institute for Stem Cell Biology and Regenerative Medicine and the National Center for Biological Sciences, both of which are world-class Indian research institutes studying fundamental biology. However, argues Venkitaraman, India needs the capacity to translate fundamental research to clinical application.

It is to help bridge this gap that the CCBT was established, with funding from the Department of Biotechnology (DBT) in India, recently supplemented by a £2 million joint award from the UK MRC and the DBT. ̽��ֱ��idea is to find innovative ways to discover ‘next-generation’ medicines against human diseases, by coupling biological research that reveals novel drug targets with approaches in chemistry and structural biology that create potential drug candidates.

Although Venkitaraman’s interest is in cancer, he predicts the work of the CCBT will be “disease agnostic”, because similar types of novel drug targets have been implicated in infectious diseases, cancer and even developmental defects.

“We desperately need to develop new medicines not just for currently problematic diseases like cancer and TB, but also for the new challenges that are being thrown at us all the time – antibiotic resistance, new infections, metabolic syndromes and diseases of ageing, for example. Nowhere is this need more critical than in emerging nations like India where the spectrum of disease is distinct from countries like the UK.”

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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How niffy nappies could help develop new weapons in fight against bacteria

jfp40 — Wed, 02 Apr 2014 21:01:26 +0000

At a time when there is growing concern about rising antibiotic resistance, the results – published in the journal PLOS ONE – could lead to new ways of combating dangerous bacteria.

For many years, people thought bacteria worked by simply consuming resources until they ran out, and then entering a stationary, non-growing, phase. Working with physicists from the Cavendish Laboratory, Hannah Gaimster and David Summers from the Department of Genetics showed that as resources decline, bacteria switch to austerity mode, individually deciding to consume less until conditions improve.

Summers and Gaimster identified this behaviour by studying indole – the chemical behind the bad smell in babies’ nappies (and also used as an ingredient in perfumes) – a key signalling molecule in bacteria.

Scientists have known for many years that bacteria use low concentrations of indole to communicate with each other. This study shows for the first time that bacteria also use the chemical in a completely different and dramatic way – producing high transient pulses of indole that accumulate within a bacterial cell and cause it to enter austerity mode.

According to Gaimster: “ ̽��ֱ��effects of low concentration of indole are subtle, but higher concentrations will do things such as abolish the ability of the cells to divide, or shut down growth completely.”

Working with Escherichia coli, Gaimster and Summers grew two cultures of the bacteria, one was the normal indole-producing E. coli and the other a mutant strain that has lost its ability to make indole.

When they stopped feeding the bacteria for 10 days, they found that the two strains coped with famine in very different ways.

“Initially the mutants seemed to do better than the wild type bacteria, but when we looked at the longer term, over 10 days the wild type’s viability declined by only one third compared with the mutants, whose viability fell by 80%. This is because without indole, the mutants could not plan ahead and weren’t able to survive as well in the long-term,” she explained.

In a second experiment, they seeded a population of wild type E. coli with 1% of the indole-lacking mutants and filmed what occurred when famine set in.

“When the food began to run out, the normal cells started doing this careful slowing down to make the food last longer, but the mutants ran riot through the culture, increasing many fold in number and eating all the food reserves. That results in disaster for everyone, because they all starve to death,” Gaimster said.

“Our results have many applications because indole plays such an important role in how bacteria respond to stress, including antibiotics. If we can understand how they use signalling systems to cope with the drugs we’re throwing at them, that should help us find new ways to get around their defences,” she said.

By discovering an entirely new way that bacteria use indole to communicate, the study could help scientists find new ways of controlling dangerous bacteria such as MRSA.

As well as opening up new modes of attacking dangerous bacteria, the study illustrates that rather than the simple creatures we assume them to be, bacteria are complex organisms with sophisticated survival strategies.

According to Summers: “I want to destroy the idea that bacteria are simple, because that’s an extraordinarily naïve view of a very sophisticated cell. Compared with humans, bacteria have been evolving for an unbelievably long time, so they will be better at being bacteria than any other organism will be at being itself.”

Bacteria 'plan ahead' by tightening their belts to help them survive looming lean periods, researchers at Cambridge have discovered.

If we can understand how bacteria use signalling systems to cope with the drugs we’re throwing at them, that should help us find new ways to get around their defences

Hannah Gaimster

Avelino Javer and Pietro Cicuta, Cavendish laboratory, ̽��ֱ�� of Cambridge

Fluorescent E. coli turn green as they produce indole

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Towards a ‘super-vaccine’ for swine bacterial diseases

bjb42 — Mon, 01 Mar 2010 09:27:59 +0000

Among the most serious diseases in pigs are those that are caused by bacteria that live in their throats, airways or tonsils and can cause severe lung infections such as pneumonia. Infected animals either die quickly or fail to grow normally, resulting in substantial economic costs to the worldwide pig industry and adding to food security concerns. Because the infections are difficult to diagnose, and current vaccines have limited efficacy, antibiotics are now in widespread use in efforts to reduce infection.

A new five-year, £5.6 million grant awarded by the Biotechnology and Biological Sciences Research Council (BBSRC) under its strategic longer and larger grant (LoLa) scheme, which supports research projects requiring ‘big’ science approaches and longer timescales, aims to develop a new vaccine and a diagnostic tool to combat the four most common bacteria that cause infections in pigs.

̽��ֱ��grant has been awarded to a consortium of researchers at the ̽��ֱ�� of Cambridge, Imperial College London, the London School of Hygiene and Tropical Medicine, and the Royal Veterinary College, as well as Huazhong Agricultural ̽��ֱ�� in China, and involves three UK government-funded agencies. ̽��ֱ��consortium also receives support from Pfizer Animal Health.

‘This combined expertise has generated a new opportunity that is highly synergistic and where real progress is possible,’ said Professor Maskell, Head of the Department of Veterinary Medicine and leader of the Cambridge component. ‘It’s also a perfect marriage between fundamental biological research and applied clinical outcomes.’

‘As a first step, we are isolating bacteria from pigs and assembling the largest ever sequenced collection of these types of bacteria,’ explained co-investigator Dr Dan Tucker. ‘From this, we’ll design and assemble appropriate super-vaccines and single-platform diagnostic tests. Crucially, these will immunise and test pigs for all four pathogens at the same time.’ In the final year of the project, field trials will be carried out in China, where dedicated facilities for this type of work are already set up.

Commenting on the timeliness of the BBSRC funding, Professor Maskell added: ‘Technical innovations and the availability of genome data have progressed to such an extent, and continue to do so, that only recently has it become possible to embark on this type of programme to find effective vaccines and diagnostics.’

For more information, please contact Professor Duncan Maskell (djm47@cam.ac.uk), Marks & Spencer Professor of Farm Animal Health, Food Science and Food Safety at the Department of Veterinary Medicine (www.vet.cam.ac.uk/).

A new multidisciplinary research programme aims to develop a single vaccine that will combat four major respiratory pathogens of pigs.

It’s a perfect marriage between fundamental biological research and applied clinical outcomes.

Professor Duncan Maskell

̽��ֱ��Pug Father from Flickr

Prize Pig

Biotechnology and Biological Sciences Research Council

̽��ֱ��Biotechnology and Biological Sciences Research Council (BBSRC) is the UK’s principal research funder across the biosciences. Its current Chair is Sir Tom Blundell, who is also Director of Research and Emeritus Professor in Cambridge’s Department of Biochemistry.

Over the past decade, BBSRC has helped achieve a step change in bioscience. Descriptive, single-problem research is increasingly being replaced by generic, predictive and systems approaches, informed by the physical, computational and social sciences. ̽��ֱ��result is that the UK has kept its world-lead in fundamental bioscience, and enhanced its capability to generate the new knowledge needed to tackle global challenges such as food security, sustainable energy and healthier ageing.

BBSRC research at Cambridge exemplifies this combination of excellence and impact. A grants and fellowships portfolio of over £50 million supports research in more than 20 departments, ranging from predictive modelling of disease epidemiology, the role of short interfering RNAs in cell regulation, data standards and software for macromolecular analysis, to mechanisms of predator vision and defensive colouration in birds. BBSRC also funds around 100 postgraduate research students including some registered with the ̽��ֱ�� at the Babraham Institute.

Cambridge hosts one of six programmes that comprise the BBSRC Sustainable Bioenergy Centre, which is a £26 million investment bringing together academics and industry to investigate sustainable methods for producing biofuels. Dr Paul Dupree in the Department of Biochemistry leads the Cambridge programme, with partners at Newcastle ̽��ֱ�� and Novozymes A/G, which seeks to improve the release of sugars from plant cell walls. An important resource for the Dupree lab, and many others across Cambridge, has been the protein-analysis capabilities of the Cambridge Centre for Proteomics, a long-term recipient of BBSRC funding.

Research projects requiring ‘big’ science approaches and longer timescales are supported by BBSRC under its strategic longer and larger (LoLa) grant scheme. One such grant to develop a pig super-vaccine was recently awarded to a consortium of researchers based at five universities, including Cambridge’s Department of Veterinary Medicine.

Ways to improve the manufacturability of viral vectors for therapeutics are currently being pursued with funding from the BBSRC-led Bioprocessing Research Industry Club.

BBSRC-funded research at Cambridge has also turned into notable innovations. One example is the massively parallel Solexa sequencing technology invented by Professor Shankar Balasubramanian and Professor David Klenerman in the Department of Chemistry, resulting in the spin-out company Solexa, which was purchased by Illumina for $600 million in 2007. ̽��ֱ��technology is revolutionising bioscience by improving the cost and speed of DNA sequencing by 1,000–10,000 fold on previous technologies. In recognition of this work, Professor Balasubramanian was recently named BBSRC Innovator of the Year 2010.

For more information and to download the BBSRC 2010–2015 Strategic Plan, please visit www.bbsrc.ac.uk/

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