̽��ֱ�� of Cambridge - antimicrobial resistance (AMR)

Monoclonal antibodies offer hope for tackling antimicrobial resistance

cjb250 — Mon, 16 Sep 2024 10:31:11 +0000

A team lead by researchers at the ̽��ֱ�� of Cambridge has developed a monoclonal antibody drug, using a technique involving genetically engineered mice, that may help prevent infection from Acinetobacter baumannii, a bacteria associated with hospital-acquired infections, which is particularly common in Asia.

A. baumannii bacteria can cause life-threatening respiratory illness and sepsis in vulnerable individuals, particularly in newborn babies whose immune systems have not fully developed. It is usually spread through contaminated surfaces, medical equipment and via contact with others. In recent years infections with strains of this bacteria that are resistant to almost every antibiotic available have become common.

Professor Stephen Baker from the Cambridge Institute of Therapeutic Immunology and Infectious Disease at the ̽��ֱ�� of Cambridge said “A. baumannii is good at sticking to medical equipment, and if people are vulnerable or don't have a particularly well-developed immune system, they can succumb to this infection and get aggressive pneumonia requiring ventilation – and in many cases, the patients can acquire the infection from the ventilation itself.

“ ̽��ֱ��bacteria are naturally resistant to many antimicrobials, but as they’re now found in hospitals, they’ve acquired resistance to almost everything we can use. In some hospitals in Asia, where the infections are most common, there isn't a single antibiotic that will work against them. They’ve become impossible to treat.”

In a study published today in Nature Communications, the team produced monoclonal antibodies using transgenic mice – mice that have been genetically-engineered to have a human-like immune system, producing human antibodies instead of mouse antibodies. They went on to show that these monoclonal antibodies were able prevent infection with A. baumannii derived from clinical samples.

Monoclonal antibodies are a growing area of medicine, commonly used to treat conditions including cancer (for example, Herceptin for treating some breast cancers) and autoimmune disease (for example, Humira for treating rheumatoid arthritis, psoriasis, Crohn's disease, and ulcerative colitis).

Usually, monoclonal antibodies are developed from the antibodies of patients who have recovered from an infection, or they are designed to recognise and target a particular antigen. For example, monoclonal antibodies targeting the ‘spike protein’ of the SARS-CoV-2 coronavirus were explored as a way of treating COVID-19.

In the approach taken by the Cambridge team, however, transgenic mice were exposed to the outer membrane of A. baumannii bacteria, triggering an immune response. ̽��ֱ��researchers then isolated almost 300 different antibodies and tested which of these was the most effective at recognising live bacteria, identifying the single monoclonal antibody mAb1416 as the best.

Professor Baker said: “Using this method, we don't infect the mice with the live bacteria, but we instead immunise them using multiple different elements and let the mouse’s immune system work out which ones to develop antibodies against. Because these mice have ‘humanised’ immune systems, we wouldn’t then need to reengineer the antibodies to work in humans.”

̽��ֱ��team treated mice with mAb1416, and 24 hours later exposed them to A. baumannii isolated from a child with sepsis in an intensive care unit. They found that those mice treated with the drug saw a significant reduction in bacterial load in their lungs a further 24 hours later, compared to mice that were not treated.

All of the isolates used to produce and test the monoclonal antibodies were from patients in Ho Chi Minh City, Vietnam, but the isolate used to test mAb1416 was taken from a patient ten years later than the other isolates. This is important because it shows that mAb1416 was protective against A. baumannii bacteria that may have evolved over time.

Professor Baker said: “Using this technique, you can take any bacterial antigen or cocktail of antigens, rather than waiting for somebody that's recovered from a particular infection – who you assume has developed an appropriate antibody response – give it to the mice and extract the antibodies you think are the most important.”

More work is now needed to understand the mechanism by which mAb1416 protects against infection, as this could allow the team to develop an even more effective treatment. Any potential new drug will then need to be tested in safety trials in animals before being trialled in patients.

Professor Baker added: “We know that monoclonal antibodies are safe and that they work, and the technology exists to produce them – what we have done is identify how to hit bacteria with them. Apart from the cost effectiveness, there's no reason why this couldn’t become a medicine within a few years. Given the emergency presented by antimicrobial resistance, this could become a powerful new weapon to fight back.”

̽��ֱ��research was funded by the Bill & Melinda Gates Foundation, the UK Medical Research Council Newton Fund, the Viet Nam Ministry of Science and Technology, and Wellcome.

Professor Baker is a fellow at Wolfson College, Cambridge.

Reference
Baker, S, Krishna, A & Higham, S. Exploiting human immune repertoire transgenic mice to identify protective monoclonal antibodies against an extensively antimicrobial resistant nosocomial bacterial pathogen. Nat Comms; 12 Sept 2024; DOI: 10.1038/s41467-024-52357-8

Monoclonal antibodies – treatments developed by cloning a cell that makes an antibody – could help provide an answer to the growing problem of antimicrobial resistance, say scientists.

We know that monoclonal antibodies are safe and that they work, and the technology exists to produce them – what we have done is identify how to hit bacteria with them

Stephen Baker

TopMicrobialStock (Getty Images)

A Petri dish with a culture of the Superbug Acinetobacter baumannii next to antibiotics

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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COVID-19 showed the importance of genomic surveillance – we need it to help fight antimicrobial resistance

cjb250 — Tue, 14 Nov 2023 23:30:16 +0000

AMR already causes substantial sickness and death worldwide, responsible for approximately 1.27 million deaths in 2019. Some estimates suggest that by 2050, it could kill as many as 10 million people each year.

Professor Sharon Peacock at the ̽��ֱ�� of Cambridge – the driving force behind the UK’s pioneering COVID-19 Genomics UK Consortium – said: “Over the past century, antibiotics have transformed our ability to treat infection and illness and reduce mortality. But bacteria are becoming increasingly resistant, and with a limited pipeline of new antibiotics, we risk effectively returning to the pre-antibiotic era where we can no longer treat infections.

“When the world was hit by the COVID-19 pandemic, we showed how powerful a tool genomic surveillance could be in helping us fight back. This work grew out of its increasing application to real-world problems such as detecting outbreaks in hospitals and in the community – including food borne outbreaks. We now need to take what we learned from the pandemic including its bold and largescale use and reapply it to the complex problem of AMR.”

̽��ֱ��genome, which is ‘written’ in DNA or RNA, consists of a string of nucleotides. Each time a copy of the genome is made, errors can arise – for example, one of the A, C, G and T nucleotides of DNA might get swapped. These changes allow scientists to create lineages – family trees – showing how the genome has evolved and spread. In the case of SARS-CoV-2, they allowed scientists to identify sources of infection, spot so-called ‘variants of concern’ and see whether public health measures such as lockdown, travel restrictions and vaccination were working.

̽��ֱ��potential to improve surveillance of AMR pathogens may be even higher than for SARS-CoV-2 as the genome data can detect and track outbreaks, provide a prediction for effective antibiotic treatment, reveal the mechanism for resistance including mutations and the acquisition of new DNA, and help understand the movement of resistance mechanisms between bacteria.

Although surveillance of AMR bacteria is already used in some settings, the growing evidence of its potential has largely not translated into routine use. Writing today in ̽��ֱ��Lancet Microbe, a working group has set out how genomic surveillance could be applied to the problem of AMR more widely, including the barriers that need to be overcome, presenting a series of recommendations including building capacity, training of existing and new workforces, standardising the way that surveillance is done to detect AMR, and agreeing equitable data sharing and governance.

̽��ֱ��group, which is funded by Wellcome, was initiated by Professor Peacock in conjunction with Wellcome SEDRIC (Surveillance and Epidemiology of Drug Resistance Infection Consortium) and delivered by a team of nearly 100 experts co-led by Professor Kate Baker and Dr Elita Jauneikaite. Five papers will be published in the same edition of the journal, highlighting the breadth of review and analysis undertaken by the team.

̽��ֱ��series covers multiple areas for the application of genomic AMR surveillance including in hospital settings to help identify outbreaks and inform infection prevention and control and informing clinical decision-making at a patient level. They also highlight applications at a public health level to detect emerging threats and to design and assess suitable interventions like vaccination. It even has the potential to track AMR pathogens moving between humans, animals, and the environment. ̽��ֱ��team also considered future innovations in genomic surveillance of AMR, looking at how the next phase of genomic technologies and analysis methods might further transform the surveillance landscape.

A number of barriers will first need to be overcome, however. These include a lack of resources and political will, and the need for more training, particularly around bioinformatics (the analysis of genome data). There are also practical barriers, including in many countries a weak epidemiological surveillance and microbiology infrastructure, poor supply chains and pricing structures, and issues around effective cooperation and data sharing.

Professor Kate Baker, ̽��ֱ�� of Cambridge, said: “We are on the cusp of realising the full potential for genomics in tackling AMR, but there is still a lot of work that needs to be done. We need the scientific, public health and political communities to work together to make this happen. AMR is an urgent problem. It is not something that will happen in years to come – it is happening now.”

Dr Elita Jauneikaite, Imperial College London, said: “We are going to be locked in an ongoing arms race with bacterial pathogens indefinitely. Genomic surveillance offers real promise to help us fight back, providing invaluable information to limit the spread and impact of AMR.”

Professor Peacock added: “It was clear from the pandemic that sequencing was a vital tool that was needed in every country worldwide. AMR is a global problem and once again we need to make sure countries worldwide are in a position both to contribute to, and benefit from genomic surveillance data.”

Janet Midega, AMR Research Lead at Wellcome and SEDRIC Board member, said: “Genomic research and surveillance are pivotal to detect pathogens and understand the transmission and trends of drug resistance in both high- and low-income settings. In order to respond effectively to this data, we need to ensure that the tools being developed are accessible and can be utilised by public health agencies around the world.”

Reference
Baker, K, et al. Overview: Harnessing genomics for antimicrobial resistance surveillance. ̽��ֱ��Lancet Microbe; 14 Nov 2023; DOI: 10.1016/S2666-5247(23)00281-1

During the COVID-19 pandemic, genomic surveillance proved vital in helping understand the evolution and spread of the SARS-CoV-2 virus. Now, an international group of researchers is calling for its potential to be harnessed to tackle antimicrobial resistance (AMR), a major global challenge that could ultimately result in many more deaths than the coronavirus pandemic.

We are on the cusp of realising the full potential for genomics in tackling AMR, but there is still a lot of work that needs to be done

Kate Baker

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Scanning electron micrograph of methicillin-resistant Staphylococcus aureus bacteria (yellow) and a dead human white blood cell (red)

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Highly antibiotic-resistant strain of MRSA that arose in pigs can jump to humans

jg533 — Tue, 28 Jun 2022 07:00:00 +0000

̽��ֱ��strain, called CC398, has become the dominant type of MRSA in European livestock in the past fifty years. It is also a growing cause of human MRSA infections.

̽��ֱ��study found that CC398 has maintained its antibiotic resistance over decades in pigs and other livestock. And it is capable of rapidly adapting to human hosts while maintaining this antibiotic resistance.

̽��ֱ��results highlight the potential threat that this strain of MRSA poses to public health. It has been associated with increasing numbers of human infections, in people who have and have not had direct contact with livestock.

“Historically high levels of antibiotic use may have led to the evolution of this highly antibiotic resistant strain of MRSA on pig farms,” said Dr Gemma Murray, a lead author of the study, previously in the ̽��ֱ�� of Cambridge’s Department of Veterinary Medicine and now at the Wellcome Sanger Institute.

She added: “We found that the antibiotic resistance in this livestock-associated MRSA is extremely stable – it has persisted over several decades, and also as the bacteria has spread across different livestock species.”

Antibiotic use in European livestock is much lower than it has been in the past. But the researchers say that ongoing reductions in antibiotic use on pig farms - due to recent policy changes - are likely to have a limited impact on the presence of this strain of MRSA in pigs because it is so stable.

While livestock-associated CC398 is found across a broad range of livestock species, it is most commonly associated with pigs. Its rise has been particularly evident in Danish pig farms where the proportion of MRSA-positive herds has increased from less than 5% in 2008 to 90% in 2018. MRSA doesn’t cause disease in pigs.

“Understanding the emergence and success of CC398 in European livestock - and its capacity to infect humans - is vitally important in managing the risk it poses to public health,” said Dr Lucy Weinert in the ̽��ֱ�� of Cambridge’s Department of Veterinary Medicine, senior author of the paper.

̽��ֱ��success of CC398 in livestock and its ability to infect humans is linked to three mobile genetic elements in the MRSA genome. These are chunks of genetic material that give the MRSA certain characteristics, including its resistance to antibiotics and its ability to evade the human immune system.

̽��ֱ��researchers reconstructed the evolutionary history of two particular mobile genetic elements called Tn916 and SCCmec that confer antibiotic resistance in MRSA, and found they have persisted in a stable way in CC398 in pigs over decades. They also persist when CC398 jumps to humans – carrying with them high levels of resistance to antibiotics commonly used in farming.

In contrast, a third mobile genetic element called φSa3 – which enables the CC398 strain of MRSA to evade the human immune system – was found to have frequently disappeared and reappeared over time, in both human-associated and livestock-associated CC398. This suggests that CC398 can rapidly adapt to human hosts.

“Cases of livestock-associated MRSA in humans are still only a small fraction of all MRSA cases in human populations, but the fact that they’re increasing is a worrying sign,” said Weinert.

Intensification of farming, combined with high levels of antibiotic use in livestock, has led to particular concerns about livestock as reservoirs of antibiotic-resistant human infections.

Zinc oxide has been used for many years on pig farms to prevent diarrhoea in piglets. Due to concerns about its environmental impact and its potential promotion of antibiotic resistance in livestock, the European Union will ban its use from this month. But the authors say this ban may not help reduce the prevalence of CC398 because the genes conferring antibiotic resistance are not always linked to the genes that confer resistance to zinc treatment.

MRSA was first identified in human patients in 1960. Due to its resistance to antibiotics it is much harder to treat than other bacterial infections. ̽��ֱ��World Health Organisation now considers MRSA one of the world’s greatest threats to human health.

̽��ֱ��findings are published today in the journal eLife.

̽��ֱ��research was funded by Wellcome, the Medical Research Council and the Raymond and Beverly Sackler Fund.

Reference

Matuszewska, M, Murray, GGR et al: ‘Stable antibiotic resistance and rapid human adaptation in livestock-associated MRSA.’ ELife, June 2022. DOI: 10.7554/eLife.74819

A new study has found that a highly antibiotic-resistant strain of the superbug MRSA – methicillin resistant Staphylococcus aureus – has emerged in livestock in the last 50 years, probably due to widespread antibiotic use in pig farming.

Cases of livestock-associated MRSA in humans are still only a small fraction of all MRSA cases in human populations, but the fact that they’re increasing is a worrying sign.

Lucy Weinert

Mark Holmes

Pig farm

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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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.

̽��ֱ��microbiologist tackling humanity’s next biggest killer

cg605 — Wed, 17 Nov 2021 12:43:31 +0000

Since childhood Stephen Baker says he had a grim fascination with poo. He caught the bug for microbiology and spent 12 years in Vietnam researching bacteria that cause diarrhoea. Stephen thinks that antibiotic-resistant bacteria is likely to be humanity’s biggest killer in the future. But says that if we keep doing the science, we have hope.

̽��ֱ��scientist reducing the rise of superbugs by talking to farmers

cg605 — Fri, 06 Nov 2020 15:42:17 +0000

Chioma Achi is worried about the global misuse of antibiotics in agricultural practices. Her work helping farmers in Nigeria to reduce infection in livestock and use fewer antibiotics in animal feed was highlighted in the recent Vice-Chancellor’s Research Impact and Engagement Awards.