Clostridioides difficile (C. diff), a type of bacteria which often affects people who have taken antibiotics, is responsible for approximately 2,000 deaths annually in the UK.

Researchers from the University of Sheffield and the University of Manchester have found C. diff is able to evolve high levels of vancomycin resistance very quickly - in less than two months the bacteria could tolerate 32 times the normally effective antibiotic concentration.

Currently, the antibiotics used to treat C. diff damage beneficial gut bacteria, leading to a high reinfection rate—up to 30 per cent of patients treated with vancomycin experience a second infection within weeks, with the likelihood of further relapses increasing thereafter.

Despite vancomycin's critical role within UK healthcare, routine monitoring for resistance in clinical settings is lacking, so resistance may be emerging under the radar in hospitals. If widespread resistance were to arise it would remove this critical treatment option from UK healthcare.

Antimicrobial resistance (AMR) has been identified by the World Health Organisation (WHO) as one of the top global public health and development threats. It is estimated that bacterial AMR was directly responsible for 1.27 million global deaths in 2019 and contributed to 4.95 million deaths.

Jessica Buddle, PhD student at the University of Sheffield and lead author of the study, said: “Our findings highlight the need for vigilant monitoring of vancomycin resistance in UK hospitals. Unchecked resistance could contribute to the large number of patients who have a relapsing infection after successful treatment with vancomycin. More research is essential to inform healthcare policy and determine if vancomycin remains the best treatment option.

“Our ongoing work aims to understand the extent and mechanisms of resistance development, simulate these conditions within the complex human gut ecosystem, and collaborate with UK epidemiologists to identify potential resistance signatures in hospitals.

“These efforts are crucial to prevent a future where antibiotics are no longer a viable option for treating bacterial infections and infections that are readily treatable today, become life-threatening once again.”

Although this rapid evolution is concerning, resistant strains exhibited reduced overall fitness, potentially limiting their clinical threat. The resistant strains also commonly had defects in sporulation. Sporulation is essential for C. diff to transmit from one person to the next and to survive on surfaces in hospitals.

Future work will seek to understand this interplay between resistance and the ability of the bacteria to cause severe disease. Researchers will be able to leverage this knowledge to improve surveillance of emerging resistance in hospitals.

Professor Michael Brockhurst from The University of Manchester said: “Our study highlights the value of using lab-based pathogen evolution to understand clinical drug resistance. This can reveal not only which genetic mutations cause resistance, but also the associated fitness costs that might limit the success of resistant strains in the clinic. Such fitness costs are a pathogen’s Achille’s Heel and could potentially be exploited to devise new treatments that reduce the burden of drug resistant infections in the future.” 

Read the full paper in the journal PLOS Biology

The research, funded by the Biotechnology and Biological Sciences Research Council’s (BBSRC) strategic Longer and Larger (sLoLa) grants programme, takes the first major step towards understanding complex microbial communities and will support the move towards a more sustainable and Net Zero future.

The University is one of four institutions to receive a share of £18 million from the BBSRC to support adventurous research aimed at tackling fundamental questions in bioscience.

The project, worth £5.4 million, builds on the work of the 91ֱ�� Microbiome Network - a network that brings together the leading microbiome science expertise from across the University to deliver a step-change in understanding microbial communities, regardless of habitat.

Lead researcher, Professor Sophie Nixon, BBSRC David Phillips and Dame Kathleen Ollerenshaw Fellow at The University of Manchester, said: “Microbial communities, often called microbiomes, are found in almost every habitable environment on the planet. They exert a significant influence on each of these environments, whether that be the soil we grow our food, in the guts of animals, or even in extreme environments like geothermal springs – our target environment for this project. However, microbiomes are inherently complex and challenging to study, and their ‘rules of life’ remain obscure.

“Recent technological advances have allowed researchers to study the interactions between members of microbiomes for the first time. Yet, we have barely scratched the surface of resolving how these interactions affect the structure, function, and stability of the community as a whole.   

Over five years, the researchers from The University of Manchester and the Earlham Institute will concentrate on low-diversity communities inhabiting geothermal springs, using a powerful combination of biochemical, ‘omics, and synthetic biology approaches to uncover the rules that govern microbial life in communities.

Using a tractable model system, the team aim to engineer the microbial community both as a learning tool to test emerging hypotheses, such as the ways in which microbes depend on or hinder one another, and as a testbed for future biotechnological development.

Ultimately, the findings will facilitate the engineering of bespoke microbial communities to be used for a plethora of important applications, including new ways to bio-convert CO2 emissions into socio-economically beneficial compounds, contributing toward a more sustainable and Net Zero future. 

Professor Guy Poppy, Interim Executive Chair at BBSRC, said: “The latest investment by BBSRC’s sLoLa award programme represents a pivotal step in advancing frontier bioscience research.

“These four world-class teams are poised to unravel the fundamental rules of life, employing interdisciplinary approaches to tackle bold challenges at the forefront of bioscience.

“By fostering collaboration and innovation, we aim to catalyse ground-breaking discoveries with far-reaching implications for agriculture, health, biotechnology, the green economy and beyond.”

The University of Manchester’s research team includes seven researchers from the Faculty of Science and Engineering (five of which are based in the flagship 91ֱ�� Institute of Biotechnology), two from the Faculty of Biology, Medicine and Health, and one from the Earlham Institute - a life science research institute based in Norwich.

New research on an enzyme that is essential for photosynthesis and all life on earth has uncovered a key finding in its structure which reveals how light can interact with matter to make an essential pigment for life.

The work gives a structural understanding of how a light activated enzyme involved in chlorophyll synthesis works. Light activated enzymes are rare in nature, with only three known. This enzyme in particular, called protochlorophyllide oxidoreductase or ‘POR’, is responsible for making the pigment vital for chlorophyll in plants. Without chlorophyll, there is no photosynthesis and no plant life.

Understanding the structure of the POR enzyme gives a rare glimpse of how a natural light-activated enzyme works. Chemists and bio-scientists alike have been fascinated by light activation of biological catalysis for many years and understanding how light can drive enzyme reactions has been a major challenge.

The revealed structure shows how the architecture of the enzyme allows one of the reactants to capture light and channel it to drive a crucial biological reaction involved in chlorophyll synthesis. Understanding these fundamental concepts should have major implications for the design of new light-activated chemical and biochemical catalysts which are increasingly important in the use of enzymes in chemical manufacture.

The research led by The University of Manchester, together with colleagues in China (, , and Qi Institute), is published today in the journal . Professor Nigel Scrutton said of the new discovery: “These studies reveal how the POR enzyme brings about light-driven reduction of the pigment Pchlide. Our studies provide a structural basis for harnessing light energy to drive catalysis in this important chlorophyll biosynthetic enzyme, which is crucial for light-to-chemical energy conversion and energy flow in the biosphere.”

Dr Derren Heyes ran several of the experiments for the new research, he said: “The crystal structure of this important light-activated enzyme has proven to be elusive for many years. Our current work provides the crucial missing link between protein structure and reaction chemistry and paves the way for detailed computational studies of the reaction in the future.”

Demonstrating such a fundamental aspect of biological life for the first time tells us how the process within the cells is carried out in order to allow photosynthesis to occur. The team discovered that light energy activates one of its substrates, protochlorophyllide, a precursor of chlorophyll, within the enzyme to drive ‘downstream’ bond breaking and making reactions.

This new discovery shows we are still unravelling the core building blocks of life which pre-date humans by billions of years. This major scientific breakthrough provides a unique structural and physical insight into a fundamental reaction in nature. This could open the door to the possibility of bioengineering artificial light-activated enzymes in the future.

An international team of researchers including scineitsts from The University of Tübingen, the German Center for Infection Research (DZIF) and The University of Manchester have achieved a breakthrough in the decoding of multi-resistant pathogens. The team led by Professor Andreas Peschel and Professor Thilo Stehle was able to decode the structure and function of a previously unknown protein used by dreaded pathogens such as Staphylococcus aureus like a magic cloak to protect themselves against the human immune system. The study was published in Nature 

Dr Guoqing Xia and his PhD student Mr Wanchat Sirisarn, from the Division of infection, immunity and respiratory medicine,  contributed to this study. Infections caused by bacteria such as Staphylococcus aureus cause many deaths worldwide. Staphylococcus aureus strains resistant to the antibiotic methicillin (MRSA for short) are particularly feared in hospitals. According to a study published at the beginning of November, there were around 670,000 diseases caused by multi-resistant pathogens in the EU alone in 2015 and 33,000 patients died.

Normally, our immune system copes well with pathogens such as bacteria or viruses. However, sometimes the defensive strategies of the human body fail, especially in immunocompromised patients. Most antibiotics are meanwhile ineffective against resistant pathogens. Effective replacement antibiotics and a protective vaccine against MRSA are not yet in sight. A precise understanding of the defence mechanisms could therefore lead to new therapies against the bacteria.

Researchers at the University of Tübingen have now described how MRSA bacteria become invisible to the immune system. They were able to show that many of the particularly frequent MRSA bacteria have acquired a previously unknown protein that prevents the pathogens from being detected by antibodies. The Tübingen scientists gave the protein the name TarP (short for teichoic acid ribitol P).

"TarP alters the pattern of carbohydrate molecules on the pathogen surface in a so far unknown way," explained Professor Andreas Peschel from the Interfaculty Institute of Microbiology and Infection Medicine at the University of Tübingen. "As a result, the immune system is unable to produce antibodies against the most important MRSA antigen, teichoic acid," said Peschel. “The immune system is ‘blinded’ and loses its most important weapon against the pathogen.”

Reprogrammed by phages

The researchers from Tübingen assume that the bacterial camouflage is the result of an exchange between the pathogens and their natural enemies, known as bacteriophages. Phages are a class of viruses that attack bacteria, use them as host cells and feed on them. In this case, phages seem to have reprogrammed their host using the TarP protein and thus altered the surface of the bacterium.

The first authors of the study, David Gerlach and Yinglan Guo, succeeded in clarifying the mechanism and structure of TarP. "We now have a detailed understanding of how the protein functions as an enzyme on the molecular level," said Gerlach. The structure-function analysis of TarP forms an excellent basis for the development of new drugs that block TarP allowing the immune system to detect the pathogens. An interdisciplinary approach, involving scientists from Denmark, Germany, Great Britain, Italy, the Netherlands and South Korea, was particularly important for the success of this work.

"The discovery of TarP came as a complete surprise to us. It explains very well why the immune system often has no chance against MRSA," said Professor Thilo Stehle from the Interfaculty Institute of Biochemistry. "The results will help us to develop better therapies and vaccines against the pathogens." Peschel referred to the recently approved Tübingen Cluster of Excellence "Controlling Microbes to Fight Infections" and the close cooperation with the German Center for Infection Research: "These outstanding networks will help us to further advance the research of MRSA and TarP."

Gerlach, Guo et al, 2018, Methicillin-resistant Staphylococcus aureus alters cell wall glycosylation to evade immunity. Nature, DOI : 10.1038/s41586-018-0730-x

Scientists at The University of Manchester have shown for the first time how antibiotics can predispose the gut to avoidable infections that trigger bowel disease in mice.

The team, led by , also showed that substances derived from fibre prevent this damage to the gut, suggesting a high fibre diet could be useful when taken during and after a course of antibiotics.

The research is to be published in and funded by the Wellcome Trust and the Medical Research Council.

They tested broad spectrum antibiotics on mice to assess their impact on the gut’s microbiota, the community of microbes that live in the gastrointestinal tract.

After a week long course of antibiotics, a harmful immune reaction started that lasted at least 2 months, an equivalent, say the researchers, of many years in humans.

The immune reaction meant that significantly fewer beneficial bacteria which make ‘short chain fatty acids’, which are good for the gut, grew back.

However, short chain fatty acids, produced by the fermentation of dietary fibre by the microorganisms which live in the gut, could prevent the harmful immune response.

“Epidemiological evidence already links antibiotics given to babies and young children, when the immune system is still developing, to inflammatory bowel disease, asthma, psoriasis and other inflammatory diseases later in life,” said Dr Mann, who is based at the University’s newly launched Lydia Becker Institute of Immunology and Inflammation.

She said: “However, until now it has been hard to determine cause and effect, especially with the time lag between taking the antibiotics and the development of disease later in life.

”This study helps explain the link through understanding the biological processes involved.

“Inflammatory bowel disease in particular has multiple causes but one of the triggering factors in many people has been infections such as Salmonella or E coli.

“We show that after antibiotics, mice are more susceptible to these types of infections, and do not mount the proper immune response to clear the infection.”

The gut is the largest source of bacteria in the body, where trillions of harmless bacteria critical for maintaining a healthy immune system live.

However, when antibiotics are taken orally, they deplete a massive community of bacteria in the intestines.

She added: “Not all patients taking antibiotics will get these diseases, and that’s because most people need a genetic predisposition to get them.

“And it’s very important that patients continue their antibiotics as these drugs are critical in clearing bacterial infections that can persist and cause serious health problems if left untreated.

“But what we’re saying is that antibiotics must only prescribed when absolutely needed for bacterial infections.

“Antibiotics, for example, are useless against viral infections such as those that cause the common cold, flu and many chest infections.”