Newly discovered virus can kill resistant bacteria

The Danish creeks, Odense Å and Lindved Å, have surprised researchers and students at SDU by containing previously unknown virus species.

"We have found five new species that we believe are unknown to science," said associate professor Clare Kirkpatrick, who studies bacterial stress-response at the Department of Biochemistry and Molecular Biology at University of Southern Denmark.

The somewhat surprising discovery was made during the coronavirus pandemic, when some of Kirkpatrick's students could not carry out their normal microbe studies in the laboratory and therefore went on field trips to local creeks to see if they had any interesting microbes to offer.

The fact that viruses exist in nature is not surprising, as they are the world's most widespread organism. They are everywhere and part of all kinds of microbial cycles and ecosystems, but the fact that five potentially new species have appeared in local creeks, did surprise Clare Kirkpatrick.

While four of the five have not yet had their genome mapped in a genome sequencing, one species has now been fully sequenced, scientifically described, named and published in Microbiology Resource Announcements. The name is Fyn8.

Many viruses are so-called bacteriophages (or phages), meaning that they kill bacteria, and Fyn8 is no exception. It can attack and kill the bacteria Pseudomonas aeruginosa.

Pseudomonas aeruginosa is a bacterium found naturally in soil and water. It is normally harmless towards healthy people, but like many other bacteria it has developed resistance to antibiotics and is found in hospitals.

For example, patients with wounds (like burn patients) and ventilator patients are at risk of getting an infection that cannot be fought with antibiotics.

The researchers have no doubt that Fyn8 can effectively kill Pseudomonas aeruginosa:

"We could see it with the naked eye: Clear holes appeared in the layer of Pseudomonas aeruginosa bacteria in our petri dishes, where Fyn8 had infected the bacterial cells, killed them, multiplied and proceeded to attack the next."

Considering that the world is facing a resistance crisis, where more people will die from an infection with resistant bacteria than from cancer, the new finding is of course interesting and raises the question; Can phages help us in the fight against resistant bacteria?

Research in this field has been uncommon until recently, both in academic research institutions and in pharmaceutical companies. In the past and in other parts of the world however, there has been some research, and phages have also been used to treat infections in Eastern European countries in particular.

The phages were discovered at the beginning of the 20th century by researchers who had their bacterial cultures destroyed by virus infections.

The benefits of that discovery were obvious, but antibiotics, not phages, became the most widespread cure against bacterial infections.

One reason was perhaps that antibiotics were easy to produce and easy to use, while the phages were difficult to isolate and give to patients.

Another reason was probably also that an antibiotic dose could kill many different bacteria, while a phage only matches with a single bacterial species.

"But today it is relatively easy to make precision medicine for the individual patient. First you find out what exact bacteria a patient is infected with -- and then you can treat the patient with exactly the phage that will kill the bacteria," explained Clare Kirkpatrick.

She adds that this strategy works even on bacteria which are resistant to all known antibiotics.

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Can we save more lives if we let resistant bacteria live?

Antibiotic resistance is a ticking bomb under public health. WHO predicts that in 2050 more people will die from infections than from cancer -- and we are talking about infections that we today consider harmless; infections that occur in a cut or wound -- or perhaps cystitis.

The reason is that bacteria are masters at adapting. When their existence is threatened, they mutate into a new and improved version of themselves that can no longer be threatened by eg antibiotics. Consequently, many disease-causing bacteria today are resistant to antibiotics.

"That's bacteria for you. They always find a way! Of course, resistance will occur; that's how evolution works," says professor and head of research, Birgitte Kallipolitis, who studies disease-causing bacteria at the Department of Biochemistry and Molecular Biology at University of Southern Denmark.

The talents of fatty acids

And that's exactly why, like other researchers around the world, she thinks it's time to find new ways to fight or neutralize the perpetually mutating bacteria.

For some years now, she and her research group have studied a particular type of fatty acid, which has proven itself interesting in this context. The researchers use listeria as a bacterial model to test the effect of these fatty acids. Elsewhere in the world, colleagues are using salmonella and cholera bacteria for similar tests.

The particular fatty acids are interesting not only because they can kill the listeria bacteria in Kallipolitis' laboratory, but they can also turn off their ability to infect and spread infection.

The researchers' experiments have shown that the fatty acids have an antimicrobial effect, ie that they can kill listeria bacteria. At first, this sounds good, but then there is the mutation thing; trying to kill the bacteria only makes it mutate into a new and resistant version of itself.

Enter the special talent of the fatty acids: They can make the resistant bacteria harmless, so that no infection occurs at all.

"Thus, the resistant bacterium is no longer a bacterium that we must try to kill -- instead, we prevent it from spreading and making us sick," Birgitte Kallipolitis explains.

No more spreading

The concept of making a disease-carrying bacterium unable to spread or make us sick is called turning off its virulence.

When you turn off the virulence of a bacterium, you prevent it from producing proteins like adhesins and invasins, which the bacterium needs to attach to a cell so that it can enter the cell.

"If a listeria bacterium cannot enter a cell, it cannot spread, and then no infection will occur," Birgitte Kallipolitis explains.

Extra help for the elderly and weak

The Listeria bacteria in Kallipolitis' experiments are only harmless as long as their virulence is switched off. When they are no longer exposed to the fatty acids that turn off their virulence, they regain the ability to spread

"But this may be the extra help that allows a patient to cope with an infection. Antivirulent medication or supplements could be good for the prevention of infections, especially in the elderly and weak," says Birgitte Kallipolitis.

The fatty acids that she and her colleagues work with, are so-called medium and long free fatty acids.

In nuts, plants and seeds

"We have especially focused on the free fatty acids, palmitoleic acid and lauric acid, which are found in nuts, seeds, plants and milk, etc. In our experiments, they show an antivirulent effect," she says.

Kallipolitis points out that you cannot eat your way to an antivirulent effect by, for example, eating nuts and seeds containing palmitoleic acid and lauric acid.

"The fatty acids must be in the free form, and that does not generally occur in food. You can buy free fatty acids as supplements but be aware that most fatty acids in supplements are locked and not in the free form.

"We do not yet know if you can achieve the effect by consuming free fatty acids. Maybe the fatty acids are metabolized before they reach the battle ground in the intestinal system, where the fight against many resistant bacteria takes place. Maybe we need pharmacists or chemists to find a way to transport the fatty acids to the scene of the battle," she explains.

Hence, a special dietary supplement or tablet is not just around the corner, she emphasizes. Before we get there, a number of tests are needed.

"The next step will be to test the antivirulence effect in a laboratory system reminiscent of the human intestinal system; here we will add listeria bacteria and see if the fatty acids will make them avirulent. If this works, it goes on to mouse experiments, and eventually it can hopefully be used prophylactically in humans," says Birgitte Kallipolitis.

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Giant leap taken in fighting antibiotic resistance

Scientists may have made a giant leap in fighting the biggest threat to human health by using supercomputing to keep pace with the impressive ability of diseases to evolve.

A new study by an international team, co-led by Dr Gerhard Koenig from the University of Portsmouth, tackled the problem of antibiotic resistance by redesigning existing antibiotics to overcome bacterial resistance mechanisms.

About 700,000 people are estimated to die every year because of antibiotic resistant bacteria, and that number is expected to rise to millions.

Without effective antibiotics, life expectancy is predicted to drop by 20 years.

The race has been on for many years to develop new antibiotics to fight disease faster than a disease can evolve.

Computers have been used in drug design for decades, but this is the first study to use a multi-pronged computer-guided strategy to make a new antibiotic from an existing one which bacteria have outwitted.

The research is published in PNAS.

Dr Koenig, a computational chemist and first author on the paper, said: "Antibiotics are one of the pillars of modern medicine and antibiotic resistance is one of the biggest threats to human health. There's an urgent need to develop new ways of fighting ever-evolving bacteria.

"Developing a new antibiotic usually involves finding a new target that is essential for the survival of a wide range of different bacteria. This is extremely difficult, and only very few new classes of antibiotics have been developed in recent times.

"We have taken a simpler approach by starting from an existing antibiotic, which is ineffective against new resistant strains, and modifying it so it's now able to overcome resistance mechanisms."

The team has shown that their best drug candidate, which is yet to undergo clinical trials, is up to 56 times more active for the tested bacterial strains than two antibiotics on the World Health Organisation's (WHO) list of essential medicines, erythromycin and clarithromycin.

Dr Koenig said: "Not only is our best candidate more effective against the tested targets, but it also shows activity against the three top ranked bacteria from the WHO priority list where the tested existing antibiotics don't work.

"It's only a matter of time until bacteria develop counterstrategies against our counterstrategies and become resistant to the new antibiotic, so we will have to keep on studying bacterial resistance mechanisms and develop new derivatives accordingly."

The hope of this new work lies in showing that the resistance mechanisms of bacteria can be addressed in a systematic way, allowing science to continually fight back with a computational evolution of new antibiotics.

Dr Koenig said: "Our computers are becoming faster with every year. So, there is some hope that we will be able to turn the tide.

"If computers can beat the world champion in chess, I don't see why they should not also be able to defeat bacteria."

The international team, including Nobel Prize laureate Ada Yonath, carried out the research at the Max-Planck-Institut für Kohlenforschung, the Weizmann Institute, and the universities of Duisburg-Essen, Bochum and Queensland.

They developed a strategy to simulate many aspects of a redesigned antibiotic at the same time, including how soluble it is, how effective it is at entering into the bacteria, and how efficient it is at blocking their protein production.

The computational work outlined in the research was done in a matter of weeks on one of the top supercomputers in Europe, but it took the international team several years to verify experimentally that their approach was indeed correct.

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Organic meat less likely to be contaminated with multidrug-resistant bacteria

Meat that is certified organic by the U.S. Department of Agriculture is less likely to be contaminated with bacteria that can sicken people, including dangerous, multidrug-resistant organisms, compared to conventionally produced meat, according to a study from researchers at the Johns Hopkins Bloomberg School of Public Health.

The findings highlight the risk for consumers to contract foodborne illness -- contaminated animal products and produce sicken tens of millions of people in the U.S. each year -- and the prevalence of multidrug-resistant organisms that, when they lead to illness, can complicate treatment.

The researchers found that, compared to conventionally processed meats, organic-certified meats were 56 percent less likely to be contaminated with multidrug-resistant bacteria. The study was based on nationwide testing of meats from 2012 to 2017 as part of the U.S. National Antimicrobial Resistance Monitoring System (NARMS).

In order for meat to be certified organic by the USDA, animals can never have been administered antibiotics or hormones, and animal feed and forage such as grass and hay must be 100 percent organic. A longstanding concern about antibiotic use in livestock and livestock feed is the increased prevalence of antibiotic-resistant pathogens. To monitor this trend, in 1996 the federal government developed NARMS to track antibiotic resistance in bacteria isolated from retail meats, farmed animals, and patients with foodborne illness in the U.S.

For their study, the Bloomberg School research team analyzed U.S. Food and Drug Administration-NARMS data from randomly sampled chicken breast, ground beef, ground turkey, and pork for any contamination and for contamination by multidrug-resistant organisms. The analysis covers four types of bacteria: Salmonella, Campylobacter, Enterococcus, and Escherichia coli.

The study covered a total of 39,348 meat samples, of which 1,422 were found to be contaminated with at least one multidrug-resistant organism. The rate of contamination was 4 percent in the conventionally produced meat samples and just under 1 percent in those that were produced organically.

The study was published May 12 in Environmental Health Perspectives.

"The presence of pathogenic bacteria is worrisome in and of itself, considering the possible increased risk of contracting foodborne illness," says senior author Meghan Davis, DVM, PhD, associate professor in the Department of Environmental Health and Engineering at the Bloomberg School. "If infections turn out to be multidrug resistant, they can be more deadly and more costly to treat."

The analysis also suggested that the type of processing facility may influence the likelihood of meat contamination. Meat processors fall into three categories: exclusively organic, exclusively conventional, or those that handle both organic and conventional meats -- so-called "split" processors. The study found that among conventional meats, those processed at facilities that exclusively handled conventional meats were contaminated with bacteria one-third of the time, while those handled at facilities that processed both conventional and organic meats were contaminated one-quarter of the time. The prevalence of multidrug-resistant bacteria was roughly the same in these two meat processor categories.

"The required disinfection of equipment between processing batches of organic and conventional meats may explain our findings of reduced bacterial contamination on products from facilities that process both types of meats," says Davis.

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New material to treat wounds can protect against resistant bacteria

Researchers at Chalmers University of Technology, Sweden, have developed a new material that prevents infections in wounds -- a specially designed hydrogel, that works against all types of bacteria, including antibiotic-resistant ones. The new material offers great hope for combating a growing global problem.

The World Health Organization describes antibiotic-resistant bacteria as one of the greatest threats to global health. To deal with the problem, there needs to be a shift in the way we use antibiotics, and new, sustainable medical technologies must be developed.

"After testing our new hydrogel on different types of bacteria, we observed a high level of effectiveness, including against those which have become resistant to antibiotics," says Martin Andersson, research leader for the study and Professor at the Department of Chemistry and Chemical Engineering at Chalmers University of Technology.

Research and development of the material has been ongoing for many years at Martin Andersson's group at Chalmers, growing in scope along the way, with a particular focus on the possibilities for wound care. Now, the important results are published as a scientific article in the journal ACS Biomaterials Science & Engineering.

The main purpose of the studies so far has been to explore new medical technology solutions to help reduce the use of systemic antibiotics. Resistant bacteria cause what is referred to as hospital-acquired infection -- a life-threatening condition and is increasing in incidence worldwide.

Mimicking the natural immune system

The active substance in the new bactericidal material consists of antimicrobial peptides, small proteins which are found naturally in our immune system.

"With these types of peptides, there is a very low risk for bacteria to develop resistance against them, since they only affect the outermost membrane of the bacteria. That is perhaps the foremost reason why they are so interesting to work with," says Martin Andersson.

Researchers have long tried to find ways to use these peptides in medical devices, but so far without much success. The problem is that they break down quickly when they come into contact with bodily fluids such as blood. The current study describes how the researchers managed to overcome the problem through the development of a nanostructured hydrogel, into which the peptides are permanently bound, creating a protective environment.

"The material is very promising. It is harmless to the body's own cells and gentle on the skin. In our measurements, the protective effect of the hydrogel on the antimicrobial peptides is clear -- the peptides degrade much slower when they are bound to it," says Edvin Blomstrand, doctoral student at the Department of Chemistry and Chemical Engineering at Chalmers, and one of the main authors of the article.

"We expected good results, but we were really positively surprised at quite how effective the material has proven," adds Martin Andersson.

According to the researchers, this new material is the first medical device to make successful use of antimicrobial peptides in a clinically and commercially viable manner. There are many varied and promising opportunities for clinical application.

Startup company Amferia takes the research from lab to market

In recent years, foundational research into the antimicrobial peptide hydrogel has run in parallel with commercial development of the innovation through the spin-off company Amferia AB.

The company was founded in 2018 by Martin Andersson together with Saba Atefyekta and Anand Kumar Rajasekharan, who both defended their dissertations at Chalmers' Department of Chemistry and Chemical Engineering.

The material and the idea, which is currently developed as an antibacterial wound patch, has generated interest around the world, attracting significant investment and receiving several awards. The company is working intensively to get the material to market so that it can benefit wider society.

Before the new material can benefit hospitals and patients, clinical studies are needed, which are ongoing. A CE marking of the material is expected to be completed in 2022. Furthermore, the wound patch version of the new material is undergoing trials in veterinary care, for treating pets. The company Amferia AB is already collaborating with a number of veterinary clinics around Europe where the hydrogel is now being tested.

"Amferia has recently entered into a strategic partnership with Sweden's largest distributor of premium medical & diagnostic devices to jointly launch these wound care products for the Swedish veterinary market during 2021" says Martin Andersson.

More about antimicrobial peptides and the new material

The beneficial properties of antimicrobial peptides have been known for some decades, and thousands of different varieties occurring in the natural immune systems of humans, animals and plants have been discovered. Researchers have long tried to mimic and use their natural function to prevent and treat infections without having to use traditional antibiotics. However, because the peptides are broken down as soon as they come in contact with blood or other body fluids, successful clinical usage has proved elusive. The researchers knew that smart new solutions were needed to protect the peptide from degradation. The new material in the study has been shown to work very well, allowing the peptides to be applied directly to wounds and injuries on the body, with the effect of both preventing and treating infection. The material is also non-toxic, so it can be used directly on the skin. The potential of this new material can also be seen in the flexibility that it offers for different types of products.

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New weapon against resistant bacteria

 Every day, people die from simple infections even though they have been treated with antibiotics. This is because more and more bacteria have become resistant to the types of antibiotics that doctors can prescribe.

"It's a huge societal problem and a crisis that we must solve. For example, by developing new antibiotics that can defeat the resistant bacteria," says professor of chemistry at the Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Poul Nielsen.

Resistant bacteria are not only known from pig farms, where it is becoming increasingly difficult to keep the pigsties disease-free. Hospitals are also experiencing with increasing regularity that, for example, infectious diseases cannot be controlled in patients. Thus, an infection in a surgical wound can become life-threatening even if the operation went well.

According to Poul Nielsen, it is important to be at the forefront of the development because the list of resistant bacteria will only grow, which means that the treatment options will be reduced. It is therefore important to develop alternatives that can be used when the current antibiotics no longer work.

"Resistance can occur very quickly, and then it's essential that we're ready," he says.

Together with his research assistant Christoffer Heidtmann and associate professor Janne Kudsk Klitgaard from the Department of Biochemistry and Molecular Biology as well as Clinical Microbiology, he has developed a substance that has the potential to become a new effective antibiotic, and SDU has now taken out a patent for it.

Unlike traditional antibiotics such as penicillin, sulfonamides and tetracyclines, this antibiotic is from the pleuromutilin class.

The substance is developed in a medicinal chemistry project and recently published in the Journal of Medicinal Chemistry.

The substance fights both resistant enterococcus, streptococcus and staphylococcus bacteria. The substance and the pleuromutilin class do this via a unique mechanism of action, which also causes resistance to develop at a very slow pace.

So far, the substance has been tested on bacteria and human cells. The next step towards becoming an approved drug is animal studies and then clinical studies in humans.

"If this substance is to reach doctors and patients as a drug, comprehensive and cost-intensive further development efforts are needed, which we can only initiate under the auspices of the university.

"The big pharmaceutical companies have that kind of money, but they are traditionally not interested in this kind of tasks, because they are not financially attractive," says Poul Nielsen.

According to Poul Nielsen, there are several reasons why it is not financially attractive to develop new antibiotics:

Antibiotics are only taken for days or weeks. There is more money in drugs for chronically ill people, such as antidepressants or blood pressure medicine.

Newly developed antibiotics will be backups and not used until the current antibiotics no longer work. So earnings are not just around the corner.

The bacteria can also become resistant to a new antibiotic, and then it has to be taken off the market again.

"However, this doesn't change the fact that the world community is in dire need of new effective drugs against antibiotic resistance. Maybe we should consider this a societal task, rather than a task that will only be solved if it's financially attractive," says Poul Nielsen.

He and his colleagues hope that the work of further developing their new antibiotic can continue. Whether it will happen, and whether it will be in a public or private context, only time will tell.

Resistant bacteria in Denmark

MRSA (Methicillin-resistant Staphylococcus aureus) comes from pigs, among others. May cause wound infection, abscesses, impetigo, infection of bones and joints as well as blood poisoning.

ESBL (Extended-spectrum beta-lactamase) is an enzyme that causes resistant intestinal bacteria from especially poultry, which can cause inflammation of the bladder, inflammation of the renal pelvis and blood poisoning.

Clostridium difficile is an intestinal bacterium that causes diarrhoea and is transmitted through faeces. It forms spores, which means that water, soap and alcohol have no effect.

VRE (Vancomycin-resistant enterococci) are bacteria that are born resistant to a wide range of antibiotics. VRE typically causes inflammation of the bladder but can also cause inflammation of the heart valves (endocarditis).

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