The Bristol Scientists Fighting Antibiotic Resistance

The Bristol Scientists Fighting Antibiotic Resistance

Antibiotic resistance is as grave a threat as climate change, but it gets nowhere near the amount of media attention (and the conflicting terminology doesn’t help). Modern life relies on antibiotics, the drugs used to treat bacterial infections. But bacteria are evolving resistance to antibiotics, making the infections they cause harder to treat and putting global security at risk.

If you are looking for some background reading on the topic, read the first article in this series, ‘What is Antibiotic Resistance?

In this article, we’ll look at four Bristol innovators working on tech designed to beat the bad bugs. From ‘making bacteria self-digest’ to ‘molecular tyre shredders’, we will cover the latest tech being developed in Bristol.

How to Tackle Antibiotic Resistance

Antibiotic resistance is ultimately a problem of supply and demand:

In 2013, the UK Government recommended ten actions to tackle antibiotic resistance on the supply and demand sides. Some involve regulation or raising awareness of the issue, but others clearly require technological innovation. That’s where science entrepreneurs are needed.

Recommended action
Supply Demand
Set up a global fund for early-stage research to tackle antibiotic resistance. Reduce unnecessary use of antibiotics in agriculture.
Improve investment into R&D for new antibiotics. Develop technology to quickly and accurately diagnose infections so doctors know which antibiotics to use.
Fund research into infectious diseases. Develop and use more vaccines so fewer antibiotics are needed.

 

The economic burden of developing new antibiotics is too great for small companies. Bold start-ups are addressing this crisis head on, by developing technologies to reduce the demand for the antibiotics we do have, making sure that they remain effective.

Bristol is a hub of activity for research into antibiotic resistance. Below, we’ll examine four innovators in the region, all hoping to reduce the demand for antibiotics.

Four Bristol Innovators Fighting Antibiotic Resistance

1. Folium Science – Making Bacteria Self-Digest

Karima Djacem, Synthetic Molecular Scientist at Folium, working in their lab at Unit DX.

Karima Djacem, Synthetic Molecular Scientist at Folium, working in their lab at Unit DX.

The Problem

The Problem

Agriculture is the biggest consumer of antibiotics. In the USA –

The use of sub-therapeutic antibiotics in animal production is becoming increasingly restricted across the world and consumers are rejecting meat produced using antibiotics. This means that the industry is looking for effective alternatives that will prevent the spread of undesirable gut bacteria, promote animal health, and reduce human zoonosis (disease crossover from animals into humans). Currently, the range of options available to producers are not fully effective in removing unwanted bacteria.

Many countries have now banned the use of antibiotics as growth promoters in animals, however in countries where their use is still permitted, this will contribute to an increased  risk of antibiotic resistance in bacteria.

The Technology

By selectively removing unwanted bacteria , Folium’s patented ‘Guided Biotics’® could  reduce the need for antibiotics in agriculture. The technology harnesses the natural CRISPR-Cas9 system.

Some bacteria use a nuclease enzyme (Cas) to cut the DNA of attacking organisms. Guided Biotics redirect this mechanism so that undesirable bacteria cut their own DNA. This causes unwanted bacteria to self-digest, specifically removing them and leaving “good” bacteria intact. Although CRISPR is more widely known as a gene editing tool, the action of Guided Biotics does not involve any gene editing of the target bacteria.

Folium Science’s Guided Biotics technology has many advantages:

Typical antibiotics Guided Biotics
Specificity Kill ‘friendly’ bacteria along with those that cause disease. This can damage animal health. Designed to target only bacteria that cause disease.
Likelihood that bacteria will become resistant Bacteria have become resistant to every antibiotic. The chance of resistance developing is very low (10-23) because there are multiple DNA targets.
Ease of redesign if resistance occurs Very difficult – it took over a decade for chemists to redesign vancomycin. Trivial – it’s much easier to change an RNA sequence than the molecular structure of a drug.
Crossover with human medicine Many antibiotics used in agriculture are critically important for human health. When resistance develops in animals, it spreads to humans. None.

 

Folium was founded in 2016. They’ve already proved that their technology works in five independent studies.

Ed Fuchs, CEO, says:

‘At  Folium Science, we’ve pioneered a platform that can reduce the need to use antibiotics in agriculture. Guided Biotics are selective and precise, will promote animal wellbeing and performance and reduce the risks of resistance. We’ve proved that our technology works: now it’s time to take it to market.’

The Future

Because Guided Biotics can be designed to selectively remove many different species of bacteria, Folium Science are applying their technology to bacteria that cause diseases in important animals and plants. Folium’s priority targets for poultry are Salmonella, pathogenic E. coli and C. perfringens. They are also developing products for other zoonotic, spoilage and wastage bacteria.

In July, the company won an Innovate UK grant to develop a treatment for Xanthomonas bacteria that devastate staple crops such as cassava, rice, and soy. Folium Science is working in partnership with the John Innes Centre to develop crop protection products for use on fresh fruit and vegetables and broad acre crops. They aim to reduce crop losses and boost overall performance by promoting a productive microbiome.

Folium will launch their first product, targeting Salmonella in poultry, in 2021.

2. Vitamica – Diagnosing Dancing Bacteria

Charlotte (right) with some of the Vitamica team in their lab.

The Problem

Vitamica are developing rapid diagnostic tools for bacterial infections.

All too often, antibiotics are given to people who don’t need them. A study published in December 2019 shows that up to 43% of antibiotic prescriptions in the USA may be unnecessary. The majority of antibiotics that GPs prescribe are for patients experiencing flu-like symptoms. Most of these infections are viral, and antibiotics don’t work against viruses.

The solution isn’t to simply reduce the number of antibiotics prescribed – we need to make sure that patients with a genuine need receive antibiotics. UK policies to reduce antibiotic prescriptions are likely to blame for the dramatic increase in hospital admissions for urinary tract infections since 2001.

In the UK, 74% of antibiotics are prescribed by GPs, who make educated guesses about what might be causing their patient’s symptoms. In the minority of cases where a diagnostic test is used, the technology used hasn’t changed since the 1960s. Bacteria are grown from patient samples to test which antibiotics will work against them. This process takes up to three days, which is unthinkable for urgent cases. Even then, current diagnostics are inaccurate: the test for urinary tract infections only catches infections half the time, so patients are often told nothing is wrong with them.

“We can’t wait to see our device in the hands of clinicians. Ultimately we want prescribers to use our system to choose an effective antibiotic the first time, which will improve patient recovery and help to fight antibiotic resistance.”

Dr Charlotte Bermingham, CTO at Vitamica

Rapid diagnostic tests that can be delivered at the point-of-care, the GP’s surgery or pharmacy, are critical to reducing the demand for antibiotics. These technologies need to be able to identify which bacterium is causing an infection, and which antibiotics will work against it, in minutes instead of days.

Lord Jim O’Neill, an antibiotic resistance expert, says:

“As time creeps by, I increasingly think that diagnostics are perhaps the single biggest potential game-changer in the fight against [antibiotic resistance]… The pressures of commerce and society to overprescribe are never ending, and we need objective indicators to stop pressurising doctors.”

The Technology

Scientists in Switzerland recently discovered a fluctuation in bacteria that relates to metabolism. Vitamica use an imaging technique developed by Dr Antognozzi, the start-up’s Chief Scientific Officer, that can image those fluctuations in real-time in single cells.

A laser is used to illuminate part of the surface of a bacterial cell. The cell scatters the laser light, which is detected by a camera. Living bacteria jiggle around, which changes the recorded signal, producing a shimmering effect. These changes can be monitored in real-time, so that the effects of antibiotic treatment (whether the bacteria are killed) can be seen in seconds.

Images showing the difference between live and dead bacteria on a standard optical microscope and using Vitamica's microscope. Vitamica's images show clear movement from the live cell that is not visible in the standard microscope's images.

Images showing the difference between live and dead bacteria on a standard optical microscope and using Vitamica’s microscope. Image: Vitamica

Recently, Vitamica have improved the speed of their technique by streamlining sample preparation and automating their process. Within four hours they can test whether a raw sample will respond to five antibiotics. This is a huge improvement over the three days required for culture-based testing. Vitamica have tested their technology on bacteria isolated from the clinic and directly on infected urine samples.

The Future

Vitamica have won awards from The Longitude Foundation, Innovate UK, Medilink SW and SETsquared. In February 2019, the company was awarded an NIHR grant to develop a cartridge for processing and testing multiple samples in parallel, making their method even quicker. Vitamica want to create a diagnostic tool that doctors can use with minimal human input, and have begun to integrate artificial intelligence into their system to this end.

To date, Vitamica have focused on urinary tract infections, but they plan to adapt their approach to tackle bloodstream infections. A quick diagnosis in sepsis is vital to save lives.

Dr Charlotte Bermingham, CTO, says:

‘For the last year, we’ve been improving and proving the speed and reliability of our technology. Now that we have a strong foundation, we can build on it by taking out method into real-world settings and putting it into practice. We can’t wait to see our device in the hands of clinicians. Ultimately we want prescribers to use our system to choose an effective antibiotic the first time, which will improve patient recovery and help to fight antibiotic resistance.’

3. FluoretiQ – Detecting Bacteria with Fluorescent Velcro

FluoretiQ scientists in the lab at Unit DX.

FluoretiQ scientists in the lab at Unit DX.

The Problem

Urinary Tract Infections present an unrelenting burden on public health as one of the most common bacterial infections, with an estimated 150 million cases per year reported worldwide. UTI’s are the second highest cause of antibiotic prescription and many patients will receive an empirical antibiotic treatment without confirmation of bacterial infection.

The Technology

FluoretiQ are developing NANOPLEX™ technology for rapid identification of bacterial infections. This technology can reduce bacterial identification from 48-72 hours to under 15 minutes, delivering the sensitivity of the lab at the speed and convenience of the dipstick.

When you have a bacterial infection, bacteria must find a way to attach themselves to their human host. They do so in a very similar way to Velcro, bacterial ‘hooks’ recognise human ‘loops’ and adhere to the surface of cells to establish the infection.

FluoretiQ are exploiting this interaction in reverse – by mimicking these ‘loops’ on the surface of human cells their probes can recognise bacteria ‘hooks’ allowing for their identification in clinical urine samples.

The technology combines two parts. The first element is a fluorescent nanomaterial probe engineered to recognise one bacterial species over another. The second element is a Quantum-enhanced detection module that allows fluorescent detection without the need for incubation or amplification of the bacterial signal.

The result is a fluorescent readout that confirms if bacteria is present, which kind, and how many, all within 15 minutes.

The approach has three steps:

  1. A patient sample is mixed with probes that target specific bacteria.
  2. Probe-labelled bacteria are separated from unlabelled species.
  3. Bacteria bound to probes are measured by Quantum-enhanced fluorescent detection.

A confocal image of E.coli labelled with FluoretiQ probes (green) and membrane tracker (red).

Nanoplex will identify 90% of uropathogenic bacteria in urinary tract infections and is undergoing development with clinical samples at regional pathology laboratories.

Neciah Dorh, CEO, says:

“Even with new drugs under development, the only way to safeguard the future is to develop the right diagnostic tools to allow us to quickly identify bacteria at the point of consultation. Nanoplex can offer this information to the physician at the point of care, reducing the need for empirical antibiotic use”

The Future

FluoretiQ are currently focused on urinary tract infections, but plan to expand their focus to a wider range of infectious disease areas. Product development is well underway and FluoretiQ hope to launch their first product in late 2021.

4. The Su Group – Molecular Tyre Shredders

The Problem

Surgeons use titanium implants to replace joints and repair bones because of its strength and because the body doesn’t reject it. Unfortunately, bacteria attach themselves to these implants and multiply. These bacteria quickly form a biofilm by producing a sticky goop of proteins and carbohydrates. Bacteria in biofilms start working together to survive, protecting themselves from the immune system and antibiotics. These bacteria cause inflammation around the implant, destroy tissue, and spread throughout the body, causing serious infections.

The only way to treat these infections is to surgically remove the implant and put the patient on a long course of strong antibiotics. This problem increases the demand for antibiotics and the risk of resistance. In the UK, there are nearly 800,000 hip replacements every year. Up to 17.5% get infected and fail, each costing £25,000 on average.

The Technology

Rather than relying on antibiotics, Professor Su’s group at the University of Bristol have taken inspiration from nature. Cicadas have evolved a way to keep their wings clean from bacteria that might infect them. Their wings are covered with tiny spikes which pierce bacterial cells, killing them within three minutes.

Professor Su’s group have developed a process for coating the surface of titanium with similar spikes. They designed two patterns:

  • Spears – densely packed short spikes similar to the cicada’s wing.
  • Pockets – longer spikes which twist together into larger pockets.

Image: Prof. Su’s paper in Scientific Reports. Licenced under CC BY 4.0.

The researchers tested their designs against polished titanium to see if they could kill bacteria that tried to grow on the surfaces. Bacteria found it more difficult to attach themselves to the spear pattern, and the first wave that did were pierced and killed. But a layer of dead cells built up on which new bacteria could grow and form a biofilm.

However, the pocket pattern was more effective. Bacteria initially adhered to the rims of the pockets, which are blunt. As they divided, they pushed each other into the pockets, where they were either pierced by or squeezed between the longer spikes. The dead cells in the pockets decayed before new cells could grow on them. After six days, five times fewer bacteria were seen on the pocket-patterned surface compared to polished titanium, and half of those cells were dead.

Image showing microscopic (SEM and FIB-SEM) images of bacteria being popped by both varients of Professor Su's technology. First, the spike-type, secondly the pocket-type. The second appears to be more effective.

Image: Prof. Su’s paper in Scientific Reports. Licenced under CC BY 4.0.

The Future

Professor Su’s group are continuing to work on a variety of antibacterial surfaces. Their designs need to be refined, but if they reach the clinic, they could make implants much safer, and stop antibiotics from being wasted.

Professor Su says:

‘Antibiotic resistance is a complex problem, one that calls for collaboration – between scientists, doctors and entrepreneurs. Bristol is a centre of excellence for research in this space, and a real melting pot. We’re a creative city, and you can see that in the range of solutions our scientists are pursuing.’

Fighting Antibiotic Resistance in Bristol

Bristol is at the centre of the fight against antibiotic resistance. The city boasts:

  • Internationally-renowned universities producing world-class antibiotic resistance research.
  • Innovative spin-out and start-up companies with bold ideas to solve the problem.
  • A network of science and technology incubators to help these companies grow and bring their technologies to market.

Learn more about antibiotic resistance by reading the previous instalment in this series. You can also follow the companies on Twitter at the links below:

Folium | Vitamica | FluoretiQ

By | 2020-02-28T10:36:59+00:00 February 24th, 2020|Antibiotic Resistance Mini Series|