INEOS Oxford Institute

Scientists and researchers take the fight to the superbugs

3
min 2022

Now scientists at the Ineos Oxford Institute have helped to identify a potential future drug that could extend the life of ‘last resort’ antibiotics.

Oxford institure lab 2.jpg

IN January 2021 INEOS committed £100 million to Oxford University amid fears that a growing, ‘silent pandemic’ of antimicrobial resistance would end modern medicine as we know it. A year on, scientists, based at the Ineos Oxford Institute, have made a promising discovery.

Carbapenems are vital, often ‘last resort’, antibiotics that are used to treat serious infections, such as sepsis and pneumonia, when all others have failed.

Despite that, some bacteria have found a way to render those carbapenems useless by producing enzymes called metallo-betalactamases (MBLs), leading to a rise in superbugs.

But new collaborative research, conducted by scientists from the Ineos Oxford Institute and several institutions across Europe, has found that indole carboxylates, a new class of enzyme blockers, can stop those enzymes working, leaving the antibiotic free to attack and kill bacteria, such as E. coli, in the lab and in infections in mice.

The researchers first screened hundreds of thousands of chemicals to see which would attach tightly to the metallo-beta-lactamases enzymes to stop them working – and which didn’t react with any human proteins.

By zooming in to take a closer look at how they work, the researchers found that these potential drugs attached to the enzymes in a completely different way to any other drugs because they copied how the antibiotic behaved with those enzymes.

The researchers then chemically changed aspects of the drugs to make them as effective as possible and tested them, in combination with carbapenems, against multi-drug resistant bacteria in both dishes in the lab and in mice.

“The potential new drugs, in combination with carbapenems, were found to be many times more potent at treating severe bacterial infections than carbapenems alone,” said Professor Schofield.

Oxford Institute lab.jpg

Antimicrobial resistance is currently responsible for about 700,000 deaths every year, but it threatens to get much, much worse, with fears that 10 million people could die every year by 2050 from common infections.

“It is a massive problem because collectively we haven’t been making enough new clinically useful antibiotics,” he said.

“As a society we must find ways both to make new antibiotics and protect the ones we have. The alternative is that routine modern medicine will be disrupted in a manner simply too horrendous to conceive.”

INEOS’ £100 million, which was used to set up the Ineos Oxford Institute, will support research into the growing resistance to antibiotics.

The money will enable more than 50 researchers to address the overuse and misuse of antibiotics, collaborate with other global leaders and develop new drugs for people and animals.

“With the fantastic support we have received from INEOS, we can replicate the latest drug discovery programme within the institute for multiple different bacterial targets and applications,” said Professor Tim Walsh, Academic Lead (Microbiology) at the Ineos Oxford Institute.

This latest research is the culmination of years of work and is a long way from being a proven solution.

But if indole carboxylates can be developed, tested and made into safe, human medicines, they could extend the effectiveness and lifespan of some of our current antibiotics and save lives all over the world.

Professor Tim Walsh said the discovery also proved that academia, given the space to create, could produce something amazing.

“That’s what we have seen here,” he said. “And we hope to make many more similar promising discoveries as the institute grows over the years.”

“This clever, Trojan Horse trick allowed these potential drugs to be highly effective against a very wide range of MBL-producing superbugs,” said Professor Christopher Schofield, Academic Lead (Chemistry), at the Ineos Oxford Institute at the University of Oxford.

Scientists, based at the Ineos Oxford Institute, have made a promising discovery which could extend the life of 'last resort' antibiotics

‘This clever, Trojan Horse trick allowed these potential drugs to be highly effective against a very wide range of MBL-producing superbugs’ - Professor Christopher Schofield, Academic Lead (Chemistry), at the Ineos Oxford Institute at the University of Oxford

Penicillin

The discovery of Penicillin and its purification into the first antibiotic in the early 1940s was one of the greatest medical advances of the 20th century.

Antibiotics changed the course of medical history, saving countless lives at the end of the Second World War, making childbirth safe for the first time in human history and allowing the creation of all modern surgery and cancer treatment that we benefit from today.

Following the discovery of Penicillin there was a “golden age” of antibiotic discovery lasting several decades.

Sadly, this era has finished, and we are left with a dwindling stock of medicines that are becoming ever less effective as bacteria naturally develop resistance to their actions.

Society needs to continue working hard to keep hold of these medical gains, and avoid returning to a pre-antibiotic era when a simple cut could be fatal.

The Ineos Oxford Institute for Antimicrobial Research was established to advance the search for solutions to one of the biggest public health challenges of our time. Researchers are working in the lab, in the field and with the public to discover new ways to prevent and treat drug resistant infections.

Conservation methods begin to bear fruit as team continues to focus on the best ways to save this incredible species from extinction. CONSERVATION methods – adopted by the INEOS-backed Six Rivers Project to try to save the Atlantic salmon – are beginning to bear fruit. Recent work has led to an improvement in the number of juveniles in the Sela river, which has long been a safe haven for this threatened species. “The management of fishing pressure has also played a significant role here,” said Pete Williams, INEOS’ Director of Technology. All fish caught must be released, and anglers are allowed to use light fishing tackle only. “We are confident that by changing traditional fishing habits, we can enhance both the quality of all the rivers and improve the life of the fish that inhabit them,” he said. Icelandic rivers are world renowned for their salmon fishing and attract enthusiasts from all over the world every year. But if the salmon disappear, a source of income for those living in remote parts of North East Iceland vanishes too. INEOS Chairman Sir Jim Ratcliffe has, for years, been working with the former Strengur Angling Club, now part of the Six Rivers Project. They are working to ensure that profit from the world-class salmon fishing business will be reinvested in the conservation work to protect the species locally and beyond. “In essence the fishing will provide the means to protect the local environment,” said Pete. The Six Rivers Project, which was initiated by Jim, is working with experts from Iceland’s Marine and Freshwater Institute and Imperial College London on a ‘multi-faceted’ conservation programme. Salmon ladders have been built to allow the salmon to reach new spawning grounds further up the rivers. Eggs have been planted in new areas. Adult fish have been relocated to new parts of the rivers, where competition for food may not be as fierce. And botanists have been planting native vegetation along the riverbanks which has increased the food supply in the rivers. The team also tagged 1,000 smolts – maturing salmon – so that scientists could track and monitor their behaviour. From that research alone, they discovered that half of smolts in the Vesturdalsa died before they even reached the sea – and very few, just 13 in 1,000, of the tagged smolts returned to spawn. “All these conservation measures have set a new standard in Iceland,” said Pete. “But there is much more to do in this long-term project.” The team, though, remain confident that, with careful management, they can reverse the decline in the wild Atlantic salmon which used to thrive in Iceland – and provide insights for protecting the species elsewhere. “It is important that we share our findings with other groups around the world,” said Pete, who is co-ordinating the academic research. “Conservation resources are limited so we need to ensure we’re not unnecessarily repeating work done elsewhere.” As part of the team’s desire to share their findings, INEOS hosts an annual Six Rivers International Conference in Reykjavik every year. In September 2021 academics from Canada, Norway, England, Iceland and beyond met to compare research. “Ultimately, we have the same aim,” said Pete. “We all want to leave the environment and habitat in better shape than we found it.” Experts from Iceland’s Marine and Freshwater Institute and Imperial College London are working on the ‘multi-faceted’ conservation programme as part of the Six Rivers Project, which was initiated by INEOS Chairman Sir Jim Ratcliffe. www.sixrivers.is ‘Our conservation measures have set a new standard in Iceland’ - Pete Williams, INEOS’ Director of Technology  

3 min read

INEOS Oxford Institute

The accidental discovery by Alexander Fleming of a mouldy petri-dish in 1928 kickstarted a 20 year journey to develop the world’s first mass-produced antibiotic. But little progress has been made since the 1980s to develop new drugs to combat the growing ‘silent pandemic’ of antimicrobial resistance. Now scientists at the Ineos Oxford Institute have helped to identify a potential future drug that could extend the life of ‘last resort’ antibiotics. IN January 2021 INEOS committed £100 million to Oxford University amid fears that a growing, ‘silent pandemic’ of antimicrobial resistance would end modern medicine as we know it. A year on, scientists, based at the Ineos Oxford Institute, have made a promising discovery. Carbapenems are vital, often ‘last resort’, antibiotics that are used to treat serious infections, such as sepsis and pneumonia, when all others have failed. Despite that, some bacteria have found a way to render those carbapenems useless by producing enzymes called metallo-betalactamases (MBLs), leading to a rise in superbugs. But new collaborative research, conducted by scientists from the Ineos Oxford Institute and several institutions across Europe, has found that indole carboxylates, a new class of enzyme blockers, can stop those enzymes working, leaving the antibiotic free to attack and kill bacteria, such as E. coli, in the lab and in infections in mice. The researchers first screened hundreds of thousands of chemicals to see which would attach tightly to the metallo-beta-lactamases enzymes to stop them working – and which didn’t react with any human proteins. By zooming in to take a closer look at how they work, the researchers found that these potential drugs attached to the enzymes in a completely different way to any other drugs because they copied how the antibiotic behaved with those enzymes. The researchers then chemically changed aspects of the drugs to make them as effective as possible and tested them, in combination with carbapenems, against multi-drug resistant bacteria in both dishes in the lab and in mice. “The potential new drugs, in combination with carbapenems, were found to be many times more potent at treating severe bacterial infections than carbapenems alone,” said Professor Schofield. Antimicrobial resistance is currently responsible for about 700,000 deaths every year, but it threatens to get much, much worse, with fears that 10 million people could die every year by 2050 from common infections. “It is a massive problem because collectively we haven’t been making enough new clinically useful antibiotics,” he said. “As a society we must find ways both to make new antibiotics and protect the ones we have. The alternative is that routine modern medicine will be disrupted in a manner simply too horrendous to conceive.” INEOS’ £100 million, which was used to set up the Ineos Oxford Institute, will support research into the growing resistance to antibiotics. The money will enable more than 50 researchers to address the overuse and misuse of antibiotics, collaborate with other global leaders and develop new drugs for people and animals. “With the fantastic support we have received from INEOS, we can replicate the latest drug discovery programme within the institute for multiple different bacterial targets and applications,” said Professor Tim Walsh, Academic Lead (Microbiology) at the Ineos Oxford Institute. This latest research is the culmination of years of work and is a long way from being a proven solution. But if indole carboxylates can be developed, tested and made into safe, human medicines, they could extend the effectiveness and lifespan of some of our current antibiotics and save lives all over the world. Professor Tim Walsh said the discovery also proved that academia, given the space to create, could produce something amazing. “That’s what we have seen here,” he said. “And we hope to make many more similar promising discoveries as the institute grows over the years.” “This clever, Trojan Horse trick allowed these potential drugs to be highly effective against a very wide range of MBL-producing superbugs,” said Professor Christopher Schofield, Academic Lead (Chemistry), at the Ineos Oxford Institute at the University of Oxford. Scientists, based at the Ineos Oxford Institute, have made a promising discovery which could extend the life of 'last resort' antibiotics ‘This clever, Trojan Horse trick allowed these potential drugs to be highly effective against a very wide range of MBL-producing superbugs’ - Professor Christopher Schofield, Academic Lead (Chemistry), at the Ineos Oxford Institute at the University of Oxford Penicillin The discovery of Penicillin and its purification into the first antibiotic in the early 1940s was one of the greatest medical advances of the 20th century. Antibiotics changed the course of medical history, saving countless lives at the end of the Second World War, making childbirth safe for the first time in human history and allowing the creation of all modern surgery and cancer treatment that we benefit from today. Following the discovery of Penicillin there was a “golden age” of antibiotic discovery lasting several decades. Sadly, this era has finished, and we are left with a dwindling stock of medicines that are becoming ever less effective as bacteria naturally develop resistance to their actions. Society needs to continue working hard to keep hold of these medical gains, and avoid returning to a pre-antibiotic era when a simple cut could be fatal. The Ineos Oxford Institute for Antimicrobial Research was established to advance the search for solutions to one of the biggest public health challenges of our time. Researchers are working in the lab, in the field and with the public to discover new ways to prevent and treat drug resistant infections. INEOSOXFORD.OX.AC.UK

3 min read