Antibiotic alternatives rev up bacterial arms race

From predatory microbes to toxic metals, nature is inspiring new ways to treat infections.

More than eight decades have passed since Alexander Fleming’s discovery of a fungus that produced penicillin — a breakthrough that ultimately spawned today’s multibillion-dollar antibiotics industry. Researchers are now looking to nature with renewed vigour for other ways of fighting infection.

Few new antibiotics are in development, and overuse of existing ones has created resistant strains of deadly bacteria. “We need a change from what we have,” says Stephen Baker, head of medicinal chemistry for antibacterials at Glaxo­SmithKline in College­ville, Pennsylvania.

Baker will talk about some of the alternatives to antibiotics on 2 June at the American Society for Microbiology’s annual meeting in New Orleans, Louisiana. Here are a few of the therapies that scientists are exploring.

Gene-editing enzymes

CRISPR, a gene-editing technique that has taken the scientific world by storm, is based on a strategy that many bacteria use to protect themselves against phages. Researchers are turning that system back on itself to make bacteria kill themselves.

Normally, the bacteria detect and destroy invaders such as phages by generating a short RNA sequence that matches a specific genetic sequence in the foreign body. This RNA snippet guides an enzyme called Cas9 to kill the invader by cutting its DNA.

Scientists are now designing CRISPR sequences that target genomes of specific bacteria, and some are aiming their CRISPR kill switches at the bacterial genes that confer antibiotic resistance.

Predatory bacteria

Bacteria cause infection, but some can also fight it by preying on fellow microbes. Several researchers are beginning to test these predatory bacteria in animal models and cell cultures.

The best-known species, Bdellovibrio bacteriovorus, is found in soil. It attacks prey bacteria by embedding itself between the host’s inner and outer cell membranes, and begins to grow filaments and replicate. “It’s like going into a restaurant, locking the door and starting to munch away,” says Daniel Kadouri, a bacteriologist at Rutgers University in Newark, New Jersey. The host bacterium eventually explodes and releases more B. bacteriovorus into the environment.

Kadouri and others are also studying the therapeutic potential of the predatory bacterium Micavibrio aeruginosavorus. And a team has engineered the gut bacterium Escherichia coli to produce peptides that kill Pseudomonas aeruginosa, a microbe that causes pneumonia.

This preliminary research is attracting attention. The Pathogen Predators programme of the US Defense Advanced Research Projects Agency, which aims to treat soldiers who contract infections on the battlefield, announced nearly US$16 million in research grants this week to groups studying predatory bacteria.

Antimicrobial peptides

Plants, animals and fungi have vastly different immune systems, but all make peptides — small proteins — that destroy bacteria. Peptides from creatures such as amphibians and reptiles, which are unusually resistant to infection, could yield new therapeutics.

Peptides with antibacterial activity have been isolated from frogs, alligators and cobras, among others, and some seem to be effective in epithelial cell cultures and at healing wounds in mice. These peptides can be modified to increase their potency, and several are in clinical trials. One, called pexiganan, based on a peptide from frog skin, is now in phase III clinical trials to treat diabetic foot ulcers.

But synthesizing such molecules can be expensive, a hurdle that scientists must overcome to bring new peptide drugs to market.


Of all the alternatives to antibiotics, phages — viruses that attack bacteria — have been used the longest in the clinic. Scientists in the Soviet Union began developing phage therapies in the 1920s, and former Soviet countries continue the tradition.

Phages have several advantages over antibiotics. Each type attacks only one type of bacterium, so treatments leave harmless (or beneficial) bacteria unscathed. And because phages are abundant in nature, researchers have ready replacements for any therapeutic strain that bacteria evolve to resist.

Mzia Kutateladze, who heads the scientific council at the Eliava Institute in Tblisi, Georgia, says that antibiotic resistance is driving more Western patients to phage-therapy clinics in Eastern Europe. The US National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, now lists phages as a research priority for addressing the antibiotic crisis. A clinical trial of a phage treatment for infections associated with burns is planned by a consortium of European centres to start this summer.

Reardon, S. Antibiotic alternatives rev up bacterial arms race. Nature 521, 402–403 (2015).


REAP Conference reports FOLIUM’s prototype digests specific unwanted bacteria in animal rearing

Support for healthy gut makes chickens thrive says co-founder at REAP

A feed additive that will protect young chicks against common bacterial infections such as salmonella and E.coli has been developed by early-stage company FOLIUM Science. Initial trials of its ‘Guided Biotic’ were seen to restore the natural balance of the healthy microbiome and revealed unexpected improvements in wellbeing.

Cambridge-based FOLIUM took part in the Start-Up Showcase at Agri-Tech East’s REAP conference (7 November), where co-founder Edward Fuchs explained how its Guided Biotics, provided alternative to antibiotics and potential solution to the growing problem of antimicrobial resistance in agriculture.

Fuchs says: “Our patented approach is highly specific, by removing only the pathogenic bacteria it leaves the animal with an intact healthy microbiome”.

“Preliminary trials in chickens indicate that reducing the disease burden improves the weight gain of the birds and removes the need to use antibiotics.”

FOLIUM is developing a new class of highly specific anti-bacterial technology based on a natural biomolecule called RNA, which is delivered directly to the pathogen.

RNA has a sequence, just like DNA, and if specifically coded it can trigger a natural process in the target bacteria that guides the bacteria’s own enzymes to degrade and digest the cell material. The process leaves no residues and so overcomes the problems of resistance.

The ‘Guided Biotic’ enables highly selective control of unwanted bacteria – even those resistant to antibiotics – while protecting closely related beneficial species of bacteria.

It can be introduced to young birds or livestock via a probiotic to treat the gut and help stabilise the microbiome. Alternatively, it can be used to counter infection, and stop the creation of biofilms – colonies of bacteria that are difficult to treat.

FOLIUM is currently focused on animal nutrition and welfare, including poultry, swine, cattle and aquaculture but sees potential for applications in plants as a bio-stimulant or novel form of seed protection.

Fuchs says that the initial trials have gone well: “We have a good collaborative network and the results from the trials have been promising, showing wider ranging benefits than we had expected.

“The next step is to investigate the benefits further with a feed to yield conversion trial and to prepare for regulatory approval. To support this we are looking for further funding alongside that of our long term investor Lundbeck Foundation.”


Animal Pharm reports FOLIUM nearing product proof-of-concept

While the company sees value for its platform across many different agricultural sectors, one keen area of interest is livestock health.

Edward Fuchs told Animal Pharm: “We focus on selective removal of the bad bacteria to be able to provide the rumen reinforcement for the good bacteria. It is so selective it can get down to specific strain-level.

“We want to develop effective solutions to maintain the health of livestock from early life by supporting the development of their microbiome while they are in our care. As antibiotics are withdrawn from use, we can now start working on feeding animals to make sure the microbiome is working properly. Establishing a new approach to disease risk management and productivity improvement.”

The Cambridge-based firm has developed its first ‘Guided Biotic’, which stabilizes the early life gut and acts as a preventative measure when added to the animal water system. Founded in 2016, Folium has been working on proof-of-concept studies in poultry this year. Previously, the company has conducted successful in vitro studies and in vivo trials with Guided Biotics. 

Edward Fuchs: “Although there has been a lot of work in the microbiome space, the animal’s biome is a complex environment – about which we are learning a great deal more.”

Folium believes its patented Guided Biotics are complementary to other feed additives such as enzymes and probiotics, which Mr Fuchs said have had relative success, as well as being a viable alternative to antibiotics.

Mr Fuchs added: “We don’t have a silver bullet but what we do have is something that will complement those products that are out there already. It can fit in with an integrated management program within livestock rearing.”

Folium is partnering with the University of Bristol and the Quadram Institute in Norwich to develop its technology in the animal health space.

While Mr Fuchs’ background is in the global food industry, his fellow co-founder and the firm’s chairman is Christian Groendahl – a doctor of veterinary medicine from the University of Copenhagen. The company also draws veterinary expertise from Professor Martin Woodward, who has over 40 years of expertise in the food animal gut microbiology and helped develop numerous vaccines for animal use including the first against Salmonella in poultry at the UK’s Animal Health and Veterinary Laboratories Agency.

Commercialization in 2019?

“We are coming to the end of initial proof-of-concept studies,” stated Mr Fuchs. “We are now collating data on how successful the microbiome is when you remove unwanted bacteria in the community. How will the microbiome behave? Is the process beneficial? Does it reduce the risk of disease transfer?

“Very early observations are positive in social behavior, faecal consistency and growth rate versus the control group.

“Although there has been a lot of work in the microbiome space, the animal’s biome is a complex environment – about which we are learning a great deal more and where our Guided Biotics will have an important role to play.”

Mr Fuchs’ comments echo that of fellow animal microbiome start-up Anizome, which spoke to Animal Pharm earlier this year about the potential for this space to redesign the way diseases are tackled.

In 2019, Folium aims to firm up its product readiness to start moving into the production and commercialisation phase. To help with these activities, Folium will be looking to secure partners from within the animal health and nutrition sectors.

The firm has been supported to date by funding from the Lundbeck Foundation, which is one of Denmark’s largest commercial foundations, and Innovate UK – a UK government initiative designed to stimulate innovation.


Innovate UK grants FOLIUM further award to develop alternatives to antibiotics in animal rearing

Innovate UK, the UK’s innovation agency has recognised the potential of FOLIUM Science’s Guided Biotics ™ by supporting a Health and Life Sciences call that will contribute to the fight against anti-microbial resistance.

In partnership with the University of Bristol, and the Quadram Institute Bioscience, the project seeks to demonstrate that FOLIUM Science’s Guided Biotics ™ can reduce the need to use antibiotics in the production of farmed animals.  The project commenced in September 2018 and will complete in April 2020.

One of the greatest challenges of modern times is the increasing prevalence of antimicrobial resistance (AMR) with the widespread use of antibiotics in animal rearing cited as a contributing factor. Not only do resistant bacteria cause productivity and animal welfare issues in the food supply chain but they pose a threat for human health too. The impact on human mortality of AMR is estimated globally at 10 million deaths a year by 2050 and no new antibiotics are currently in development.

Consequently, producers of farmed animals are under pressure to reduce their use of antibiotics yet current preventative and treatment methods for bacterial infections have yet to prove fully effective. Current options include vaccines, probiotic, prebiotic and phytochemical treatments.

FOLIUM Science has developed unique and patented technology in the form of Guided Biotics ™. Guided Biotics ™ selectively remove unwanted bacteria by harnessing enzymes in bacteria as a zootechnical feed additive. In this project FOLIUM Science, the University of Bristol and the Quadram Institute Bioscience will evaluate the effectiveness of Guided Biotics ™ to control specific pathogens and demonstrate superior effectiveness compared to other non-medical interventions.

Poultry production is the fastest growing animal production sector and has been identified as a model within which to develop new interventions that will be applicable across all animal production. Salmonella enterica and Avian Pathogenic Escherichiacoli (APEC) have a high incidence within poultry (c70%) with high prevalence of resistance along with a zoonotic risk to humans. These two gut pathogens are responsible for production losses of up to 15% and have therefore been identified as the focus of the project work. The project is led by Professor Martin Woodward, Chair of Microbiome Studies at the University of Reading with 40 years of expertise in veterinary microbiology.

FOLIUM Science CEO Ed Fuchs says “Innovate UK has recognised one of the greatest challenges of modern times represented by AMR and the potential contribution of Guided Biotics ™.The specificity of our biotechnology allows us to target only those bacteria that are harmful to animal health, leaving the good bacteria intact and stabilising the gut microbiome. Whilst this project focusses on poultry pathogens, Guided Biotics ™ can be equally effective on a broad range of bacterial species found in agriculture and aquaculture and we are already working on solutions beyond poultry production”

In line with Innovate UK’s aims to advance bioscience techniques and to increase yield and sustainability in food production, Guided Biotics ™ have the potential to reduce the cost of production via the decrease in use of antibiotics whilst improving animal health and productivity. Unlike antibiotics there is no withdrawal period after use and Guided Biotics ™ are equally effective against bacteria that are resistant to antibiotics.

Guided Biotics ™ are administered as an additive either in feed or in drinking water.

Trials are already under way demonstrating consistent in-vivo results across multiple poultry studies with up to log5 reduction in Salmonella bacteria, reducing the risk of contamination and zoonosis and leading to improvements in animal welfare, productivity and quality.

The need for alternatives to the use of antibiotics represents significant bioscience R&D and commercial opportunities. The potential cost avoidance to the livestock industry of alternatives to current treatment methods is estimated to be c£128m p.a.

This project is a new collaboration between FOLIUM Science,the University of Bristol and the Quadrum Institute Bioscience. The combination of FOLIUM Science’s Guided Biotics ™, the animal models from the University of Bristol and the genome biology expertise of the Quadram Insititute will result in tangible benefits for the food industry and the promise of a long-term contribution to the global challenge of AMR.


Nutreco recognises FOLIUM’s ambition to tackle Antimicrobial Resistance

During 2018, any small business with an innovative Feed Tech product, concept or service in pilot scale or proof-of-concept was invited to apply for the prestigious Nutreco Feed Challenge award.

All entrants were required to pass several milestones before experts selected the 10 finalists to be invited to a two-day final event on 28 and 29 May 2018 in the Netherlands.

The top three finalists were then asked to pitch at the F&A Next event in May. F&A Next is the first European platform for investors, startups and scale-ups in the food and agricultural domain.

The Nutreco Feed Tech Challenge is focused around the question ‘What is your breakthrough innovation in feeding the future that CANNOT wait’. This question represents one of Nutreco’s initiatives to contribute to the need to feed over 9 billion people in 2050.

From an entry of over 700 ideas and 52 global companies, FOLIUM Science’s Guided Biotics ™ technology was selected to take part in the final assessment. Further questioning then took place alongside the other finalists over a two day assessment.

FOLIUM Science’s CEO Ed Fuchs says “To be awarded the runner up prize from such a large and high quality entry is testament to the breakthrough nature of our technology. The future for GuidedBiotics ™ looks very exciting indeed”.

The key benefits that Nutreco identified about FOLIUM Science’s technology was the potential to tackle Antimicrobial Resistance head on with a novel technology that can be broadly applied across agricultural and animal feed businesses.


Innovate UK award asks FOLIUM to control biofilms on plants and animals

UK-based FOLIUM Science has developed a unique way to fight unwanted bacteria in animal production; remove the organisms from an animal’s gut by causing them to self-destruct.

The patented technology, being developed at the company’s research and development laboratory in Bristol, could potentially reduce the need for antibiotics in farmed animals and, therefore, help stem the growing problem of anti-microbial resistance. Its targeted action against unwanted bacteria could also be employed to maintain a healthy microbiome, which, the company believes, could mean that current antibiotic alternatives, like pre- and probiotics, will no longer be needed in the future.

This selective removal of the bacteria responsible for production issues in animal agriculture and how the process could be used to fight anti-microbial resistance was the idea behind FOLIUM Science’s creation in 2015. Founded by CEO Ed Fuchs, a former food industry executive, along with systems biology professor Morten Sommer, veterinary and human medicine expert, Dr Christian Grondahl, and patent attorney, Jasper Clube, the company has turned this concept into its own patented system called ‘Guided Biotics™’, which it plans to develop into zootechnical additives that can be added to feed or drinking water.

Through the use of CRISPR, the biological sequences that make up the bacterial immune system, FOLIUM’s system directs the organism into believing it is being attacked thereby causing it to self-destruct. FOLIUM can tailor the technology to target a specific bacterium or a defined range of bacteria, which means that, unlike the kill-all approach of many antibiotics, it can be used to remove only the unwanted bacteria in the animal’s digestive tract and leave beneficial gut flora unchanged.

Feedinfo News Service recently caught up with the company’s CEO to find out how the company sees its technology affecting the animal agriculture industry when it hits the market in late 2020 and what its role in the fight against anti-microbial resistance will be.

[Feedinfo News Service] You credit antibiotic/antimicrobial resistance in animal agriculture as a reason for establishing FOLIUM Science. In your view, has the industry made sufficient changes to slow its growth?

[Ed Fuchs] The link between the use of antibiotics in animal rearing and the rise in anti-microbial resistance is now widely recognised, hence the move away from sub-therapeutic use in feeds in many parts of the world. Recent studies have shown that many salmonella and E.coli found in chickens are resistant to a range of commonly used antibiotics. Importantly, these bacteria enter the human food chain and are potential zoonotics, meaning they can cause health problems in humans. Antibiotic resistance is estimated to contribute to the death of approximately 700,000 people at a cost of USD 40 billion annually across the globe, and is predicted to increase if current practises do not change.

Since restrictions came into force in Europe and the United States on the use of sub-therapeutic antibiotics, the industry has focused on trying to find viable and effective alternatives that will prevent the proliferation of undesirable gut bacteria and promote animal health. However, the range of options currently available to producers, whilst supportive of gut health, are less than fully effective in removing unwanted bacteria.

[Feedinfo News Service] Your approach to helping them fight these unwanted bacteria involves CRISPR. Most people will probably know it as a gene editing tool, but in bacteriology it is something different. Can you take us through what it is and how FOLIUM Science is applying it to livestock production? How reliable is this technology?

[Ed Fuchs] Guided Biotics™ are based on patented CRISPR-Cas technology. CRISPR is an acronym that describes repeating sequences of DNA that form part of the bacterial natural immune system that has developed to recognise and destroy the DNA of invading elements, such as bacterial viruses. Guided Biotics™ use CRISPR to identify and target specific sequences of DNA only in the targeted undesirable bacteria.

This natural bacterial immune system involves a nuclease enzyme (Cas) that cuts the DNA of an attacking virus. Guided Biotics™ redirect this enzymic mechanism so that undesirable bacteria cut their own DNA. This causes bacteria to self-digest, meaning that the specific unwanted bacterium is removed from the animal gut.

Although CRISPR is more widely known as a gene editing tool, the action of our technology does not involve any gene editing of the target bacteria. Guided Biotics ™ are designed to be extremely specific in targeting the unique sequences of DNA that are found only in the target organism. The data from our in-vitro and in-vivo studies shows that this can be achieved consistently and repeatedly.

Three independent in-vivo studies have conclusively proved that Guided Biotics™ can dramatically reduce salmonella bacteria in poultry. In these three studies, Guided Biotics™, designed to target all 2,400 serotypes of salmonella, were given to test groups of birds as an additive to the drinking water whilst the control groups were not given the Guided Biotic™. All birds were then exposed to a severe salmonella challenge.

Collectively, the data showed statistically significant reductions (p=0.001) in colony forming units (CFUs) of salmonella bacteria in caecal samples when comparing colonisation levels in the test groups with those of the control groups. There was an overall drop in colonisation of at least log 2 across the flock given the Guided Biotic™. Furthermore, salmonella could not be detected in 50% of the birds given the Guided Biotic™ compared to 100% detection in the control animals.

[Feedinfo News Service] Let’s turn to antibiotic/anti-microbial resistance, a subject you’ve obviously considered while developing your Guided Biotics technology. What are some of the developments that you’ve noticed while researching this field?

[Ed Fuchs] Every geography and animal group has unique issues when it comes to antimicrobial resistance and also zoonotic contamination. For example, there are, to a greater or lesser extent, issues with salmonella globally, particularly in poultry products. In regions raising broilers without sub-therapeutic antibiotics, Clostridium perfringens-mediated necrotic enteritis has become a major problem.

Conversely, in piglets Escherichia coli-mediated diarrhoea can cause serious economic losses, while Vibrio species are a particular problem in shrimp production. The list of undesirable bacteria that need control is extensive.

[Feedinfo News Service] And for a long time antibiotics was the way to do this. But, as a result of antibiotic resistance and restrictions on antibiotic use, more and more producers are turning to gut health products, like pre- and probiotics, and phytogenics. How does your technology differ from these alternative solutions in ensuring livestock health?

[Ed Fuchs] What makes our Guided Biotics™ different is that alongside being delivered via a standard probiotic, they also selectively remove undesirable bacteria from the gut, leaving the beneficial and commensal bacteria intact. This supports a positive gut microbiome by allowing these beneficial bacteria to thrive.

No other feed additive is this specific. Whilst some phytogenics, probiotics and prebiotics may have marginal suppressive and competitive exclusion effects on some pathogens this reduction is never more than marginal.

[Feedinfo News Service] In terms of cost, how competitive will your solution be when it is launched? Especially compared to these antibiotic alternatives that are already on the market?

[Ed Fuchs] Guided Biotics™ will be priced competitively with current feed additives such as pre- and probiotics. We are developing our manufacturing capability to ensure our costs of production will support this goal and we have sufficient capacity to meet projected global demand.

[Feedinfo News Service] In your opinion, will your technology replace, to some extent, current nutritional antibiotic alternatives in the future? Or do you see it playing more of a complementary role?

[Ed Fuchs] Because Guided Biotics™ will be effective in removing the undesirable bacteria in the animal gut and thus supporting the growth of positive bacteria, it will mean that some additives such as the probiotics that are currently used to give support to the gut microbiome will no longer be necessary.  For this reason we consider Guided Biotics™ as “next generation” probiotics.

[Feedinfo News Service] We understand that the first version of your technology will focus on eliminating salmonella in chickens. How far away are you from adapting it for other bacteria (like E.coli) and for the beef, pork and aquaculture industries?

[Ed Fuchs] Applications are in development for use in poultry, cattle, swine and aquaculture. Phase one priority targets for poultry applications are salmonella (all serotypes) and then C. perfringens. Salmonella can cause bird production losses and is a major zoonotic human health issue globally. C. perfringens causes necrotic enteritis that has become a significant cause of productivity losses in markets where antibiotic-free poultry is an increasingly important consumer requirement.

Subsequent products are under design for a wide range of pathogens, spoilage and wastage bacteria in all parts of animal production, agriculture and aquaculture.