Is global challenge of antibiotic resistance about to be solved on Bourn High Street?

PUBLISHED: 07:24 22 August 2017 | UPDATED: 15:09 23 August 2017

Dr Heather Fairhead, CEO and founder of Phico Therapeutic, left, in the lab. Picture: Keith Heppell

Dr Heather Fairhead, CEO and founder of Phico Therapeutic, left, in the lab. Picture: Keith Heppell

Iliffe Media Ltd

It is already killing an estimated 700,000 annually - and it’s predicted to get worse. But Dr Heather Fairhead of Phico Therapeutics may have uncovered a solution.

The bacterium Pseudomonas aeruginosa, which Phico is working on. The illustration shows polar location of flagella and presence of pili on the bacterial surfaceThe bacterium Pseudomonas aeruginosa, which Phico is working on. The illustration shows polar location of flagella and presence of pili on the bacterial surface

‘Personally, I think it’s really scary,” says Dr Heather Fairhead, the founder and CEO of Phico Therapeutics.

“Everyone is a potential patient who might need antibiotics. Even commonplace infections are becoming more resistant and it’s only going to get worse.

“We’ve got antibiotics that a few years ago were thought of as a last resort – carbapenems – and we’re getting resistance to those now. We’ve moved on to a class that people didn’t like to use because they are very toxic. They are becoming more mainstream – and we’re getting resistance to those as well.”

The World Health Organisation warns that antibiotic resistance “is one of the biggest threats to global health, food security and development today”.

Phico Therapeutics has moved to the Bertarelli Building in High Street, Bourn. Picture: Keith HeppellPhico Therapeutics has moved to the Bertarelli Building in High Street, Bourn. Picture: Keith Heppell

It says: “A growing list of infections – such as pneumonia, tuberculosis, blood poisoning and gonorrhoea – are becoming harder, and sometimes impossible, to treat as antibiotics become less effective.

“Without urgent action, we are heading for a post-antibiotic era in which common infections and minor injuries can once again kill.”

A form of tuberculosis resistant to at least four key drugs has been identified in 105 countries.

Last year, resistance was confirmed to first-line treatments for malaria in five countries in the Great Mekong area. Along the Cambodia-Thailand border, malaria has become resistant to almost all available medicines. In an age of global travel, there is a real concern that this resistance could spread. Some 193 nations have signed up to the UN declaration to tackle the threat, which has been greatly accelerated by overuse of antibiotics in humans and farm animals.

In the lab at Phico Therapeutics. Picture: Keith HeppellIn the lab at Phico Therapeutics. Picture: Keith Heppell

Given the scale of the problem, to suggest one of the best hopes for a solution lies on Bourn High Street may strain credibility. But later this year, clinical human trials will begin of a new treatment that has the potential to change our use of antibiotics forever.

SASPject is a treatment developed by Phico Therapeutics, a company founded by Dr Fairhead in 2000, and it can reasonably be described as brilliantly devious.

To understand it, first it’s important to realise that it is bacteria that become resistant to antibiotics, not humans.

“Bacteria can double in numbers every 20 minutes – and every time they do that you will get some mutations. It’s real-time evolution and happening very fast,” says Dr Fairhead.

A biofilm of antibiotic-resistant bacteriaA biofilm of antibiotic-resistant bacteria

Bacteria are broadly divided into ‘gram-positive’ and ‘gram-negative’ based on whether they have a membrane outside the cell wall.

“Gram-positive bacteria include MRSA, we are better off for treatments,” says Dr Fairhead. “But gram-negative bacteria are really hard to treat. The last new class of antibiotics for them was in the 1960s. That’s the area we are focusing on.

“We are looking at a bacterium called Pseudomonas aeruginosa that commonly causes respiratory infections such as pneumonia. Pseudomonas is inherently resistant to lots of antibiotics. It’s a very difficult bug, so that’s where our focus lies.”

Phico’s treatment makes use of the fact that bacteria – like humans – are susceptible to viruses.

Dr Heather Fairhead outside Phico Therapeutics. Picture: Keith HeppellDr Heather Fairhead outside Phico Therapeutics. Picture: Keith Heppell

“We use bacterial viruses or ‘phages’. These viruses are very specific so they will only target certain types of bacteria,” explains Dr Fairhead. “We have a virus that only attacks Pseudomonas aeruginosa and it will leave all of your other good bacteria alone.

“We take the virus and re-engineer it genetically, so we take out bits of its DNA that we don’t want in there and put in there a gene that encodes our antibiotics.

“It’s the virus that you administer to the person – it’s the drug that goes around the body. Wherever the infection is, it will stick to that bacteria and, in the way that viruses do in every infection, inject its DNA into that bacteria, only now they’re injecting the gene that we’ve put in there.

“So the virus is acting as a nano-delivery vehicle, dropping off a parcel that is the DNA for our antibiotics. Then the antibiotics get made inside the bacteria. Basically, the bacteria is really committing suicide, although they don’t know it.

Antibiotics have been over-prescribed - and are available without a prescription in some countriesAntibiotics have been over-prescribed - and are available without a prescription in some countries

“Gram negatives have a membrane outside of the cell wall that stops antibiotics getting in. But we’re using a delivery vehicle that’s specifically designed for that bacteria – so nature has already overcome that problem.”

The antibiotics – or small-acid soluble spore proteins (SASP) – work by binding to the DNA inside the bacteria. “It changes the shape of the DNA and distorts it. Without active DNA, no cell can survive,” says Dr Fairhead.

“The really unique characteristic of our antibiotic is that even when the bacteria mutates – which is what causes antibiotic resistance – it doesn’t matter. It will still stick to and inactivate the DNA so it’s very difficult to see how they would become resistant to that active part of the treatment.”

Although the treatment will not reach human trials until later this year, Dr Fairhead reports “really good results” in the lab and is “optimistic” that it will work in practice. If so, it could take four years before it reaches patients.

An illustration of antibiotic-resistant bacteriaAn illustration of antibiotic-resistant bacteria

Phico is also developing a product to tackle E.coli and Klebsiella pneumoniae – but the technology could be applied in theory to any bacterial infection.

“There won’t be any type of bacteria without viruses that can attack it. Some will be easier to work with than others but fundamentally we could attack any,” says Dr Fairhead.

“It’s relatively quick to find the virus – there are millions out there. We want ones that can attack a very broad range of strains, which takes a bit longer, but that is the shorter part of the development programme. You have to engineer it and develop your manufacturing.

“If it works, it could change the approach to antibiotic treatment.”

To date, Phico has raised £22million over 17 years.

“We’ve been funded by private individuals, and we’ve had two Wellcome Trust awards and some Innovate UK government money.

“We have 175 shareholders so I feel like I’ve hoovered up nearly every biotech investor in the country!” says Dr Fairhead.

“The plan with the product we’re developing is to get an efficacy symbol in humans as early as possible and then license that product, which would generate income. Ultimately, the aim is we would be acquired by a pharma company as we can’t take products to market ourselves.”

In the meantime, we must change our attitude and use of antibiotics.

“Over here, doctors are much more focused on not over-prescribing antibiotics but in some places in Europe and other places, like India, you can buy them over the counter,” says Dr Fairhead.

“The real problem is overusing antibiotics in animals to promote growth when they are not even ill. It’s banned in the UK but not elsewhere.”

In early July, G20 leaders said they would strive to stop this – and encourage prudent use of antibiotics. They also agreed to establish an R&D Collaboration Hub to maximise the impact of research.

Perhaps their first stop ought to be Phico’s shiny new premises on Bourn High Street.

So, should we finish the course?

After years of telling patients that they must finish a prescribed course of antibiotics to avoid triggering more virulent forms of disease, are doctors about to change their tune?

An article published last week in the British Medical Journal by 10 experts said the long-standing advice from the NHS and World Health Organisation is not sound.

Lead author Martin Llewelyn, professor of infectious diseases at Brighton and Sussex Medical School, and colleagues said: “Historically, antibiotic courses were driven by fear of undertreatment, with less concern about overuse. The idea that stopping antibiotic treatment early encourages antibiotic resistance is not supported by evidence, while taking antibiotics for longer than necessary increases the risk of resistance.”

Current advice from Public Health England is to take antibiotics “exactly as prescribed” - which leaves the decision on how long a course should be to doctors.

Stepping up the global battle

Antiobiotic resistance around the world will be more closely monitored thanks to £6.8million funding for a new Global Health Research Unit at the Wellcome Trust Sanger Institute in Hinxton.

As the Cambridge Independent reported last week, the unit, housed in the Centre for Genomic Pathogen Surveillance, will enable DNA sequencing and genomic surveillance of resistant bacteria through National laboratories in the Philippines, India, Nigeria and Colombia.

Professor Sharon Peacock, honorary faculty member at the Wellcome Trust Sanger Institute and professor of microbiology at the London School of Hygiene & Tropical Medicine, said: “With the emergence and global spread of antibiotic resistance, there is a huge need for this type of initiative. Low and middle-income countries have the greatest need for assistance, and the four that have been focused on stand to benefit enormously from the impact of this new technology in their own research and healthcare.”

An ‘Alexander Fleming moment’

Researchers at the University of Salford last month suggested they had stumbled across a potentially exciting solution to antibiotic resistance.

The team were sorting through 45,000 compounds in search of ones that might be effective against cancer stem cells, using a three-dimensional structure of the mitochondrial ribosome – first identified by Venki Ramakrishnan, a Nobel Prize winner at the MRC Laboratory of Molecular Biology in Cambridge.

Whittling the compounds down to 10 that might be effective against mitochondria, they found they also inhibited a broad spectrum of five types of common bacteria, including Streptococcus, Pseudomonas, E coli and MRSA, and killed the pathogenic yeast, Candida albicans.

Michael P Lisanti, chair of translational medicine at the University’s Biomedical Research Centre, said: “A little like Alexander Fleming, we weren’t even looking for antibiotics rather researching into new compounds that might be effective against cancer stem cells.”

Dr Federica Sotgia, co-author, said: “I think we’ve accidentally invented a systemic way of creating new antibiotics which is simple, cheap and could be very significant in the fight against superbugs.”

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