Ants recognize infected wounds and treat them with antibiotics

The Matabele ants (Megaponera analis), which are widespread south of the Sahara, have a narrow diet: They only eat termites. Their hunting expeditions are dangerous because termite soldiers defend their conspecifics -- and use their powerful mandibles to do so. It is therefore common for the ants to be injured while hunting.

If the wounds become infected, there is a significant survival risk.

However, Matabele ants have developed a sophisticated healthcare system: they can distinguish between non-infected and infected wounds and treat the latter efficiently with antibiotics they produce themselves.

This is reported by a team led by Dr Erik Frank from Julius-Maximilians-Universität (JMU) Würzburg and Professor Laurent Keller from the University of Lausanne in the journal Nature Communications.

Treatment Drastically Reduces Mortality

"Chemical analyses in cooperation with JMU Professor Thomas Schmitt have shown that the hydrocarbon profile of the ant cuticle changes as a result of a wound infection," says Erik Frank.

It is precisely this change that the ants are able to recognise and thus diagnose the infection status of injured nestmates.

For treatment, they then apply antimicrobial compounds and proteins to the infected wounds.

They take these antibiotics from the metapleural gland, which is located on the side of their thorax.

Its secretion contains 112 components, half of which have an antimicrobial or wound-healing effect.

And the therapy is highly effective: the mortality rate of infected individuals is reduced by 90 per cent, as the research group discovered.

Analysis of Ant Antibiotics is Planned

"With the exception of humans, I know of no other living creature that can carry out such sophisticated medical wound treatments," says Erik Frank.

Laurent Keller also adds that these findings "have medical implications because the primary pathogen in ant's wounds, Pseudomonas aeruginosa, is also a leading cause of infection in humans, with several strains being resistant to antibiotics."

Are Matabele ants really unique in this respect? The Würzburg researcher now wants to explore wound care behaviours in other ant species and other social animals.

He also wants to identify and analyse the antibiotics used by Matabele ants in cooperation with chemistry research groups.

This may lead to the discovery of new antibiotics that could also be used in humans.

Read more at Science Daily

Scientist uncovers roots of antibiotic resistance

Bacteria naturally adapt to various environmental stimuli and as they mutate, these changes can make them resistant to drugs that would kill or slow their growth.

In a recent article published in PLoS Genetics, UCF College of Medicine microbiologist Dr. Salvador Almagro-Moreno uncovers the evolutionary origins of antimicrobial resistance (AMR) in bacteria. His studies on the bacterium that causes cholera, Vibrio cholerae, provide insight into deciphering what conditions must occur for infectious agents to become resistant.

"How AMR occurs in bacterial populations and the pathways leading to these new traits are still poorly understood," he said. "This poses a major public health threat as antimicrobial resistance is on the rise."

Dr. Almagro-Moreno studied genetic variants of a protein found in bacterial membranes called OmpU. Using computational and molecular approaches, his team found that several OmpU mutations in the cholera bacteria led to resistance to numerous antimicrobial agents. This resistance included antimicrobial peptides that act as defenses in the human gut. The researchers found that other OmpU variants did not provide these properties, making the protein an ideal system for deciphering the specific processes that occur to make some bacteria resistant to antimicrobials.

By comparing resistant and antibiotic sensitive variants, the researchers were able to identify specific parts of OmpU associated with the emergence of antibiotic resistance. They also discovered that the genetic material encoding these variants, along with associated traits, can be passed between bacterial cells, increasing therisk of spreading AMR in populations under antibiotic pressure.

By understanding how mutations occur, researchers can better understand and develop therapeutics to combat resistant infections. Dr. Almagro-Moreno is also looking at environmental factors such as pollution and warming of the oceans, as possible causes of resistant bacteria. "We are studying the genetic diversity ofenvironmental populations, including coastal Florida isolates, to develop a new approach to understandinghow antimicrobial resistance evolves," he explained.

Read more at Science Daily

Antibiotic consumption is currently not the main driver of aminoglycoside resistance spread, study suggests

The spread of antibiotic resistance, where infectious bacteria are able to defeat the drugs intended to kill them, may not be primarily driven by antibiotic consumption, according to a study published today in eLife.

Rather, the study suggests that the prevalence of antibiotic resistance across Europe between 1997 and 2018 is mostly explained by exchanges between ecosystems, and human exchanges such as merchandise imports or travel.

The results support the idea that interventional strategies based on reducing antibiotic use should be complemented by a stronger control of exchanges, especially between ecosystems.

Antibiotic resistance represents one of the largest threats to global public health, food security and global development faced today. Due to the spread of antibiotic resistance, a growing number of infections, such as pneumonia and tuberculosis, are becoming harder to treat, leading to longer hospital stays, greater costs and increased mortality.

"Many public health agencies have recommended reducing antibiotic use in response to the challenges caused by resistance," explains co-author Léa Pradier, a former PhD student at University of Montpellier, France. Pradier conducted the study alongside Stéphanie Bedhomme, a researcher at CNRS,. "However, there are cases where developed countries have reduced their antibiotic consumption and not halted the spread of antibiotic resistance genes across bacterial populations, implying other factors are at play," continues Pradier.

To explain this, Pradier and Bedhomme set out to describe the genetic, geographical and ecological distribution of resistances to a class of antibiotics called aminoglycosides, and from this information, quantify the relative contribution of different factors driving the spread of antibiotic resistance. Aminoglycosides have limited clinical use in humans, but are often a last resort for treating multi-resistant infections. They are also commonly used in the treatment of farmyard animals, meaning that resistance to them poses a significant threat to global food security.

They utilised a computational approach to screen the genetic information of over 160,000 bacteria genomes, looking for genes encoding aminoglycoside-modifying enzymes (AMEs) -- the most common mechanism of aminoglycoside resistance. They detected AME genes in around a quarter of genomes screened, and in samples from all continents (excluding Antarctica) and all biomes investigated. The majority of AME-gene-carrying bacteria were found in clinical samples (55.3%), human samples (22.1%) and farm samples (12.3%).

Pradier and Bedhommme then focused on the distribution of AME genes across Europe, from 1997-2018, when the most detailed data was available. During this period, aminoglycoside usage remained relatively constant, but was highly variable between countries. Comparing the prevalence of AME genes between countries with different aminoglycoside usage over time, the team determined that aminoglycoside consumption was only a minor explanatory factor, with few positive or directional effects on AME gene prevalence.

Instead, the dataset implies that human exchanges through trade and migration, and exchanges between biomes, explain most of the spread and maintenance of antibiotic resistance when modelled over time, space and ecology. AME genes can be carried over continents by plant and animal products, and international trade and travellers, and may then spread to local strains of bacteria through a process called horizontal gene transfer -- the movement of genetic information between organisms. The pool of AME genes sampled from plants, wild animals and soil had the strongest overlap with other communities, suggesting these biomes are major hubs for AME gene propagation, either by horizontal resistance gene transfer or by resistant bacteria movement.

The findings suggest that the largest cause of AME gene spread is through the movement of antibiotic-resistant bacteria between ecosystems and biomes. This spread is aided by mobile genetic elements, which increase the likelihood for a genome to carry several copies of the same AME gene. This increases the expression of transferred AME genes and allows bacteria to evolve new antibiotic resistance functions through the duplicated sequences.

These findings are preliminary, as limited by the use of publicly available data, rather than deploying a dedicated sampling method. In addition, the genetic data sourced from multiple different research projects caused a sampling bias towards industrialised countries and biomes with clinical interest, leading to some locations and biomes being over-represented.

Read more at Science Daily

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.

Read more at Science Daily

How a soil microbe could rev up artificial photosynthesis

Plants rely on a process called carbon fixation -- turning carbon dioxide from the air into carbon-rich biomolecules - for their very existence. That's the whole point of photosynthesis, and a cornerstone of the vast interlocking system that cycles carbon through plants, animals, microbes and the atmosphere to sustain life on Earth.

But the carbon fixing champs are not plants, but soil bacteria. Some bacterial enzymes carry out a key step in carbon fixation 20 times faster than plant enzymes do, and figuring out how they do this could help scientists develop forms of artificial photosynthesis to convert the greenhouse gas into fuels, fertilizers, antibiotics and other products.

Now a team of researchers from the Department of Energy's SLAC National Accelerator Laboratory, Stanford University, Max Planck Institute for Terrestrial Microbiology in Germany, DOE's Joint Genome Institute (JGI) and the University of Concepción in Chile has discovered how a bacterial enzyme -- a molecular machine that facilitates chemical reactions -- revs up to perform this feat.

Rather than grabbing carbon dioxide molecules and attaching them to biomolecules one at a time, they found, this enzyme consists of pairs of molecules that work in sync, like the hands of a juggler who simultaneously tosses and catches balls, to get the job done faster. One member of each enzyme pair opens wide to catch a set of reaction ingredients while the other closes over its captured ingredients and carries out the carbon-fixing reaction; then, they switch roles in a continual cycle.

A single spot of molecular "glue" holds each pair of enzymatic hands together so they can alternate opening and closing in a coordinated way, the team discovered, while a twisting motion helps hustle ingredients and finished products in and out of the pockets where the reactions take place. When both glue and twist are present, the carbon-fixing reaction goes 100 times faster than without them.

"This bacterial enzyme is the most efficient carbon fixer that we know of, and we came up with a neat explanation of what it can do," said Soichi Wakatsuki, a professor at SLAC and Stanford and one of the senior leaders of the study, which was published in ACS Central Science this week.

"Some of the enzymes in this family act slowly but in a very specific way to produce just one product," he said. "Others are much faster and can craft chemical building blocks for all sorts of products. Now that we know the mechanism, we can engineer enzymes that combine the best features of both approaches and do a very fast job with all sorts of starting materials."

Improving on nature

The enzyme the team studied is part of a family called enoyl-CoA carboxylases/reductases, or ECRs. It comes from soil bacteria called Kitasatospora setae, which in addition to their carbon-fixing skills can also produce antibiotics.

Wakatsuki heard about this enzyme family half a dozen years ago from Tobias Erb of the Max Planck Institute for Terrestrial Microbiology in Germany and Yasuo Yoshikuni of JGI. Erb's research team had been working to develop bioreactors for artificial photosynthesis to convert carbon dioxide (CO2) from the atmosphere into all sorts of products.

As important as photosynthesis is to life on Earth, Erb said, it isn't very efficient. Like all things shaped by evolution over the eons, it's only as good as it needs to be, the result of slowly building on previous developments but never inventing something entirely new from scratch.

What's more, he said, the step in natural photosynthesis that fixes CO2 from the air, which relies on an enzyme called Rubisco, is a bottleneck that bogs the whole chain of photosynthetic reactions down. So using speedy ECR enzymes to carry out this step, and engineering them to go even faster, could bring a big boost in efficiency.

"We aren't trying to make a carbon copy of photosynthesis," Erb explained. "We want to design a process that's much more efficient by using our understanding of engineering to rebuild the concepts of nature. This 'photosynthesis 2.0' could take place in living or synthetic systems such as artificial chloroplasts -- droplets of water suspended in oil."

Portraits of an enzyme

Wakatsuki and his group had been investigating a related system, nitrogen fixation, which converts nitrogen gas from the atmosphere into compounds that living things need. Intrigued by the question of why ECR enzymes were so fast, he started collaborating with Erb's group to find answers.

Hasan DeMirci, a research associate in Wakatsuki's group who is now an assistant professor at Koc University and investigator with the Stanford PULSE Institute, led the effort at SLAC with help from half a dozen SLAC summer interns he supervised. "We train six or seven of them every year, and they were fearless," he said. "They came with open minds, ready to learn, and they did amazing things."

The SLAC team made samples of the ECR enzyme and crystallized them for examination with X-rays at the Advanced Photon Source at DOE's Argonne National Laboratory. The X-rays revealed the molecular structure of the enzyme -- the arrangement of its atomic scaffolding -- both on its own and when attached to a small helper molecule that facilitates its work.

Further X-ray studies at SLAC's Stanford Synchrotron Radiation Lightsource (SSRL) showed how the enzyme's structure shifted when it attached to a substrate, a kind of molecular workbench that assembles ingredients for the carbon fixing reaction and spurs the reaction along.

Finally, a team of researchers from SLAC's Linac Coherent Light Source (LCLS) carried out more detailed studies of the enzyme and its substrate at Japan's SACLA X-ray free-electron laser. The choice of an X-ray laser was important because it allowed them to study the enzyme's behavior at room temperature -- closer to its natural environment -- with almost no radiation damage.

Meanwhile, Erb's group in Germany and Associate Professor Esteban Vo?hringer-Martinez's group at the University of Concepción in Chile carried out detailed biochemical studies and extensive dynamic simulations to make sense of the structural data collected by Wakatsuki and his team.

The simulations revealed that the opening and closing of the enzyme's two parts don't just involve molecular glue, but also twisting motions around the central axis of each enzyme pair, Wakatsuki said.

"This twist is almost like a rachet that can push a finished product out or pull a new set of ingredients into the pocket where the reaction takes place," he said. Together, the twisting and synchronization of the enzyme pairs allow them to fix carbon 100 times a second.

The ECR enzyme family also includes a more versatile branch that can interact with many different kinds of biomolecules to produce a variety of products. But since they aren't held together by molecular glue, they can't coordinate their movements and therefore operate much more slowly.

"If we can increase the rate of those sophisticated reactions to make new biomolecules," Wakatsuki said, "that would be a significant jump in the field."

From static shots to fluid movies

So far the experiments have produced static snapshots of the enzyme, the reaction ingredients and the final products in various configurations.

"Our dream experiment," Wakatsuki said, "would be to combine all the ingredients as they flow into the path of the X-ray laser beam so we could watch the reaction take place in real time."

The team actually tried that at SACLA, he said, but it didn't work. "The CO2 molecules are really small, and they move so fast that it's hard to catch the moment when they attach to the substrate," he said. "Plus the X-ray laser beam is so strong that we couldn't keep the ingredients in it long enough for the reaction to take place. When we pressed hard to do this, we managed to break the crystals."

An upcoming high-energy upgrade to LCLS will likely solve that problem, he added, with pulses that arrive much more frequently -- a million times per second -- and can be individually adjusted to the ideal strength for each sample.

Read more at Science Daily

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.

Read more at Science Daily

DNA tangles can help predict evolution of mutations

Tangles in unwound DNA can create mutational hotspots in the genomes of bacteria, according to a new study by the Milner Centre for Evolution at the University of Bath. The study authors say these findings will help us in the future to predict the evolution of bacteria and viruses over time, which could aid vaccine design and better understanding of antibiotic resistance.

While most evolution is shaped by natural selection, where only those individuals who are adapted for their environment are able to survive and pass on their genes, a new study published in Nature Communications shows that evolution is also influenced by tangles in the DNA strands.

A team of scientists, led by the University of Bath in collaboration with the University of Birmingham, looked at the evolution of two strains of the soil bacteria Pseudomonas fluorescens (SBW25 and Pf0-1).

When the scientists removed a gene that enables the bacteria to swim, both strains of the bacteria quickly evolved the ability to swim again, but using quite different routes.

One of the strains (called SBW25), always mutated the same part of a particular gene to regain mobility.

However, the other strain (called Pf0-1) mutated different places in different genes each time the scientists repeated the experiment.

To understand why one strain evolved predictably and the other was unpredictable, they compared the DNA sequences of the two strains. They found that in the SBW25 strain, which mutated in a predictable way, there was a region where the DNA strand looped back on itself forming a hairpin-shaped tangle.

These tangles can disrupt the cell machinery, called DNA polymerase, which copies the gene during cell division, and so makes mutations more likely to happen.

When the team removed the hairpin structure using six silent mutations (without changing the sequence of the protein produced), this abolished the mutational hotspot and the bacteria started evolving in a much wider variety of ways to get back its swimming ability.

Dr Tiffany Taylor, from the Milner Centre for Evolution, said: "DNA normally forms a double helix structure, but when the DNA is copied, the strands are briefly separated.

"We've found there are hotspots in the DNA where the sequence causes the separated strands of DNA to get twisted back on themselves -- a bit like when you pull apart the strands of a rope -- this results in a tangle.

"When the DNA polymerase enzyme runs along the strand to copy the gene, it bumps into the tangle and can skip, causing a mutation.

"Our experiments show that we were able to create or remove mutational hotspots in the genome by altering the sequence to cause or prevent the hairpin tangle.

"This shows that while natural selection is still the most important factor in evolution, there are other factors at play too.

"If we knew where the potential mutational hotspots in bacteria or viruses were, it might help us to predict how these microbes could mutate under selective pressure."

Mutational hotspots have already been found in cancer cells, and the researchers plan to search for them across a range of bacterial species, including important pathogens.

This information can help scientists better understand how bacteria and viruses evolve, which can help in developing vaccines against new variants of diseases. It can also make it easier to predict how microbes might develop resistance to antibiotics.

Dr James Horton, who has recently completed his PhD at the Milner Centre for Evolution, said: "Like many exciting discoveries, this was found by accident. The mutations we were looking at were so-called silent because they don't change the resulting protein sequence, so initially we didn't think they were particularly important.

Read more at Science Daily

Cat bacteria treats mouse skin infection, may help you and your pets as well

Researchers at University of California San Diego School of Medicine used bacteria found on healthy cats to successfully treat a skin infection on mice. These bacteria may serve as the basis for new therapeutics against severe skin infections in humans, dogs and cats.

The study, published in eLife on October 19, 2021, was led by Richard L. Gallo, MD, PhD, Distinguished Professor and chair of the Department of Dermatology at UC San Diego School of Medicine, whose team specializes in using bacteria and their products to treat illnesses -- an approach known as "bacteriotherapy."

Skin is colonized by hundreds of bacterial species that play important roles in skin health, immunity and fighting infection. All species need to maintain a diverse balance of healthy skin bacteria to fight potential pathogens.

"Our health absolutely depends on these 'good' bacteria," said Gallo. "They rely on our healthy skin to live, and in return some of them protect us from 'bad' bacteria. But if we get sick, 'bad' bacteria can take advantage of our weakened defenses and cause infection."

This is the case with methicillin-resistant Staphylococcus pseudintermedius (MRSP), a bacterium commonly found on domesticated animals that becomes infectious when the animals are sick or injured. MRSP is an emerging pathogen that can jump between species and cause severe atopic dermatitis, or eczema. These infections are common in dogs and cats, and can also occur in humans, though rates of human infection vary around the world. As its name suggests, MRSP is resistant to common antibiotics and has been difficult to treat in clinical and veterinary settings.

To address this, researchers first screened a library of bacteria that normally live on dogs and cats and grew them in the presence of MRSP. From this, they identified a strain of cat bacteria called Staphylococcus felis (S. felis) that was especially good at inhibiting MRSP growth. They found that this special strain of S. felis naturally produces multiple antibiotics that kill MRSP by disrupting its cell wall and increasing the production of toxic free radicals.

"The potency of this species is extreme," said Gallo. "It is strongly capable of killing pathogens, in part because it attacks them from many sides -- a strategy known as 'polypharmacy.' This makes it particularly attractive as a therapeutic."

Bacteria can easily develop resistance to a single antibiotic. To get around this, S. felis has four genes that code for four distinct antimicrobial peptides. Each of these antibiotics is capable of killing MRSP on their own, but by working together, they make it more difficult for the bacteria to fight back.

Having established how S. felis kills the MRSP, the next step was to see whether it could work as a therapy on a live animal. The team exposed mice to the most common form of the pathogen and then added either S. felis bacteria or bacterial extract to the same site. The skin showed a reduction in scaling and redness after either treatment, compared with animals that had no treatment. There were also fewer viable MRSP bacteria left on the skin after treatment with S. felis.

Next steps include plans for a clinical trial to confirm whether S. felis can be used to treat MRSP infections in dogs. Bacteriotherapies like this one can be delivered via topical sprays, creams or gels that contain either live bacteria or purified extract of the antimicrobial peptides.

While these products are in development, what should pet owners do in the meantime?

"Don't stop washing your pets to keep these 'good' bacteria on them," said Gallo. "Skin has evolved to protect the 'good' bacteria, so soap and detergents don't usually wash the good guys off."

Read more at Science Daily

Pandemic of antibiotic resistance is killing children in Bangladesh, researchers find

Resistance to antibiotics is common and often deadly among children with pneumonia in Bangladesh, according to a new study coauthored by researchers from Massachusetts General Hospital (MGH) with colleagues at the International Centre for Diarrhoeal Disease Research, Bangladesh (abbreviated as icddr,b). This study, which appears in the journal Open Forum Infectious Diseases, offers an early warning that a pandemic of potentially deadly antibiotic resistance is under way and could spread around the globe.

The study was led by Mohammod Jobayer Chisti, MD, PhD, a senior scientist in icddr,b's Nutrition and Clinical Services Division. Chisti was inspired to conduct the research when he observed that the hospital affiliated with icddr,b was admitting more and more young children with pneumonia who were highly resistant to treatment with standard antibiotics. "At our hospital, dozens of kids died of pneumonia between 2014 and 2017, despite receiving the World Health Organization's recommended antibiotics and enhanced respiratory support," says Chisti.

Pneumonia is an infection of the lungs that causes fluid and pus to fill air sacs, producing cough, fever, trouble breathing, and other symptoms. Without effective treatment, the infection can be fatal; pneumonia is the most common cause of death in young children, according to the World Health Organization. In small children, pneumonia can be caused by viruses, but certain types of bacteria are common sources of infection, too. In the United States and other high-income countries, Staphylococcus ("staph"), Streptococcus ("strep"), and Haemophilus influenzae are the most common bacterial causes of pneumonia, which usually respond well to antibiotic therapy. Vaccines for the latter two have saved countless lives worldwide.

However, when Chisti and his colleagues examined health records of more than 4,000 children under age five with pneumonia admitted to their hospital between 2014 and 2017, they found that a very different pattern of bacterial infections was occurring. The usual staph and strep infections that commonly cause pneumonia in the United States and elsewhere were relatively rare. Among the children who had a positive culture, gram-negative bacteria were responsible for 77 percent of the infections, including Pseudomonas, E. coli, Salmonella and Klebsiella.

"That's totally different than what I'm used to in my practice in Boston," says Jason Harris, MD, MPH, co-first author of the study and chief of the division of Pediatric Global Health at the Massachusetts General Hospital for Children. Unfortunately, he adds, "the gram-negative bacteria we saw in these kids are notorious for being antibiotic resistant." To wit: Some 40 percent of the gram-negative bacterial infections in this study resisted treatment with first- and second-line antibiotics that are routinely used to treat pneumonia. More alarming, children who had antibiotic-resistant bacterial infections were 17 times more likely than others without bacterial infections to die.

Harris believes that these results are clear evidence that longstanding concerns that antibiotic resistance will become a deadly menace are no longer theoretical -- the problem has taken root. "These kids are already dying early because of antibiotic-resistant bacteria, from what would be a routine infection in other parts of the world," says Harris. "And this was at one hospital in Bangladesh. Extrapolate these findings across a country of 163 million people, and then to a larger region where antibiotic resistance is emerging, and the overall numbers are probably huge."

There is an urgent need to address factors that are promoting antibiotic resistance in Bangladesh, says Tahmeed Ahmed, PhD, executive director of icddr,b and senior author of the study. For starters, antibiotics can be purchased without a prescription in the country and many people use them to self-treat conditions such as dysentery, cold, cough and fever. Misuse of antibiotics promotes the spread of bacteria that resist the medications. "We may be able to reduce this emerging bacterial resistance by improving antibiotic stewardship, particularly in the outpatient setting," says Ahmed. Lab testing for diagnosis of bacterial infections is also inadequate in the country. "What's more, lack of access to clean water and adequate sanitation helps spread bacteria that are resistant to antibiotics," adds Ahmed. Improvements in health care infrastructure and policy changes to rein in the misuse of antibiotics are essential, he argues, though Ahmed notes that Bangladesh's health care system also needs better access to more advanced antibiotic therapies for resistant infections.

If these and other steps aren't taken now, it's only a matter of time before the problem of widespread deadly antibiotic resistance spreads around the world, notes Harris. "We know that acquisition of antibiotic resistance is very common in travelers, and that when highly resistant bacteria crop up in one part of the world, they ultimately crop up everywhere," he says, comparing the problem to another current global health care crisis. "If COVID-19 was a tsunami, then emerging antibiotic resistance is like a rising flood water. And it's kids in Bangladesh who are already going under."

Read more at Science Daily

Hundreds of antibiotic resistant genes found in the gastrointestinal tracts of Danish infants

Hundreds of antibiotic resistant genes found in the gastrointestinal tracts of Danish infants.

Danish one-year-olds carry several hundred antibiotic resistant genes in their bacterial gut flora according to a new study from the University of Copenhagen. The presence of these genes is partly attributable to antibiotic use among mothers during pregnancy.

An estimated 700,000 people die every year from antibiotic resistant bacterial infections and diseases. The WHO expects this figure to multiply greatly in coming decades. To study how antibiotic resistance occurs in humans' natural bacterial flora, researchers from the University of Copenhagen's Department of Biology analysed stool samples from 662 Danish one-year-old children.

Within the samples, the researchers discovered 409 different genes, providing bacteria with resistance to 34 types of antibiotics. Furthermore, 167 of the 409 genes found are resistant to multiple types of antibiotics, including those classified as 'critically important' by the WHO for being able to treat serious diseases in the future.

"It's a wake-up call that one-year-old children are already carrying gut bacteria that are resistant to very important types of antibiotics. New resistant bacteria are becoming more widespread due to increased antibiotic consumption. The horror scenario is that we will one day lack the antibiotics needed to treat life-threatening bacterial infections such as pneumonia or foodborne illnesses," explains Department of Biology professor Søren Sørensen, who led the study.

Antibiotic use during pregnancy is an important factor

The important factor for whether an infant had more antibiotic-resistant genes in bacteria in the gut was if the child's mother had been administered antibiotics during late pregnancy or if the year-old infant had received antibiotics in the months prior to the collection of their stool samples.

"We found a very strong correlation between a mother's antibiotic treatment during late pregnancy and of infants and gut bacteria with many resistant genes, although it appears that other influences come into play as well," says Xuan Ji Li of the Department of Biology, the study's lead author.

At the same time, the researchers found a link between how well-developed the gut flora of children were and the concentration of resistant bacteria. Well-developed gut flora equated with a lesser incidence of resistant bacteria. Previous studies from the same group of children demonstrated that the development of gut flora is linked to asthma risk later in life.

E. coli collect resistant genes

Escherichia coli (E. coli) is common in the intestine and can lead to intestinal infections. But in this study, the researchers also learned that E. coli appears to act as a main collector and a potential spreader of antibiotic-resistant genes to other gut bacteria.

The researchers also found E. coli in infants with high concentrations of resistance genes in their intestinal tracts.

Read more at Science Daily

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).

Read more at Science Daily

Detecting trace amounts of multiple classes of antibiotics in foods

 Widespread use of antibiotics in human healthcare and livestock husbandry has led to trace amounts of the drugs ending up in food products. Long-term consumption could cause health problems, but it's been difficult to analyze more than a few antibiotics at a time because they have different chemical properties. Now, researchers reporting in ACS' Journal of Agricultural and Food Chemistry have developed a method to simultaneously measure 77 antibiotics in a variety of foods.

Antibiotics can be present at trace amounts in meat, eggs and milk if the animals aren't withdrawn from the drugs for a sufficient period of time before the products are collected. Also, antibiotics can accumulate in cereals, vegetables and fruits from manure fertilizer or treated wastewater applied to crops. Consuming these foods over a long period of time could lead to increased antibiotic resistance of bacterial pathogens or to an imbalance in the gut microbiome. However, most previous monitoring methods for antibiotics in foods have been limited to a few compounds at a time, usually within a single class of antibiotics with similar structures and chemical properties. Other methods have analyzed multiple antibiotics in only a single food type, such as eggs or milk. Yujie Ben and colleagues wanted to develop a time- and cost-effective method that could detect a wide range of antibiotics in different types of foods.

The researchers added trace amounts of 81 antibiotics from seven categories to vegetable samples and tested 20 different methods for extracting the drugs from the food. Only one extraction process, which involved treating freeze-dried, homogenized food samples with an acidified acetonitrile solution and a mixture of magnesium sulfate and sodium acetate, allowed the researchers to isolate 77 of the antibiotics. After establishing that their method was sensitive and accurate with spiked antibiotics in several foods, the team applied it to store-bought samples of wheat flour, mutton, eggs, milk, cabbage and bananas, detecting a total of 10 antibiotics. One of them, roxithromycin, was detected at trace amounts in all six food types. The new method should help with understanding, monitoring and regulating antibiotic levels in foods, the researchers say.

From Science Daily

Synthesis of potent antibiotic follows unusual chemical pathway

 Images of a protein involved in creating a potent antibiotic reveal the unusual first steps of the antibiotic's synthesis. The improved understanding of the chemistry behind this process, detailed in a new study led by Penn State chemists, could allow researchers to adapt this and similar compounds for use in human medicine.

"The antibiotic thiostrepton is very potent against Gram-positive pathogens and can even target certain breast cancer cells in culture," said Squire Booker, a biochemist at Penn State and investigator with the Howard Hughes Medical Institute. "While it has been used topically in veterinary medicine, so far it has been ineffective in humans because it is poorly absorbed. We studied the first steps in thiostrepton's biosynthesis in hopes of eventually being able to hijack certain processes and make analogs of the molecule that might have better medicinal properties. Importantly, this reaction is found in the biosynthesis of numerous other antibiotics, and so the work has the potential to be far reaching."

The first step in thiostrepton's synthesis involves a process called methylation. A molecular tag called methyl group, which is important in many biological processes, is added to a molecule of tryptophan, the reaction's substrate. One of the major systems for methylating compounds that are not particularly reactive, like tryptophan, involves a class of enzymes called radical SAM proteins.

"Radical SAM proteins usually use an iron-sulfur cluster to cleave a molecule called S-adenosyl-L-methionine (SAM), producing a "free radical" or an unpaired electron that helps move the reaction forward," said Hayley Knox, a graduate student in chemistry at Penn State and first author of the paper. "The one exception that we know about so far is the protein involved in the biosynthesis of thiostrepton, called TsrM. We wanted to understand why TsrM doesn't do radical chemistry, so we used an imaging technique called X-ray crystallography to investigate its structure at several stages throughout its reaction."

In all radical SAM proteins characterized to date, SAM binds directly to the iron-sulfur cluster, which helps to fragment the molecule to produce the free radical. However, the researchers found that the site where SAM would typically bind is blocked in TsrM.

"This is completely different from any other radical SAM protein," said Booker. "Instead, the portion of SAM that binds to the cluster associates with the tryptophan substrate and plays a key role in the reaction, in what is called substrate-assisted catalysis."

The researchers present their results in an article appearing Jan. 18 in the journal Nature Chemistry.

In solving the structure, the researchers were able to infer the chemical steps during the first part of thiostrepton's biosynthesis, when tryptophan is methylated. In short, the methyl group from SAM transfers to a part of TsrM called cobalamin. Then, with the help of an additional SAM molecule, the methyl group transfers to tryptophan, regenerating free cobalamin and producing the methylated substrate, which is required for the next steps in synthesizing the antibiotic.

"Cobalamin is the strongest nucleophile in nature, which means it is highly reactive," said Knox. "But the substrate tryptophan is weakly nucleophilic, so a big question is how cobalamin could ever be displaced. We found that an arginine residue sits under the cobalamin and destabilizes the methyl-cobalamin, allowing tryptophan to displace cobalamin and become methylated."

Next the researchers plan to study other cobalamin-dependent radical SAM proteins to see if they operate in similar ways. Ultimately, they hope to find or create analogs of thiostrepton that can be used in human medicine.

"TsrM is clearly unique in terms of known cobalamin-dependent radical SAM proteins and radical SAM proteins in general," said Booker. "But there are hundreds of thousands of unique sequences of radical SAM enzymes, and we still don't know what most of them do. As we continue to study these proteins, we may be in store for many more surprises."

Read more at Science Daily

How antibiotics interact

 It is usually difficult to predict how well drugs will work when they are combined. Sometimes, two antibiotics increase their effect and inhibit the growth of bacteria more efficiently than expected. In other cases, the combined effect is weaker. Since there are many different ways of combining drugs -- such as antibiotics -- it is important to be able to predict the effect of these drug combinations. A new study has found out that it is often possible to predict the outcomes of combining certain antibiotics by quantitatively characterizing how individual antibiotics work. That is the result of a joint study by Professor Tobias Bollenbach at the University of Cologne with Professor Gasper Tkacik and the doctoral researcher Bor Kavcic at the Institute of Science and Technology Austria. The paper 'Mechanisms of drug interactions between translation-inhibiting antibiotics' has been published in Nature Communications.

'We wanted to find out how antibiotics that inhibit protein synthesis in bacteria work when combined with each other, and predict these effects as far as possible, using mathematical models,' Bollenbach explained. As head of the research group 'Biological Physics and Systems Biology' at the University of Cologne, he explores how cells respond to drug combinations and other signals.

Bacterial ribosomes can gradually translate the DNA sequence of genes into the amino acid sequence of proteins (translation). Many antibiotics target this process and inhibit translation. Different antibiotics specifically block different steps of the translation cycle. The scientists found out that the interactions between the antibiotics are often caused by bottlenecks in the translation cycle. For example, antibiotics that inhibit the beginning and middle of the translation cycle have much weaker effects when combined.

In order to clarify the underlying mechanisms of drug interactions, the scientists created artificial translation bottlenecks that genetically mimic the effect of specific antibiotics. If such a bottleneck is located in the middle of the translation cycle, a traffic jam of ribosomes forms, which dissolves upon introducing another bottleneck at the beginning of the translation cycle. Using a combination of theoretical models from statistical physics and experiments, the scientists showed that this effect explains the drug interaction between antibiotics that block these translation steps.

Tobias Bollenbach concluded: 'A quantitative understanding of the effect of individual antibiotics allows us to predict the effect of antibiotic combinations without having to test all possible combinations by trial and error. This finding is important because the same approach can be applied to other drugs, enabling the development of new, particularly effective drug combinations in the long term.'

From Science Daily

New way to make bacteria more sensitive to antibiotics discovered

 Researchers from Singapore-MIT Alliance for Research and Technology (SMART), MIT's research enterprise in Singapore, have discovered a new way to reverse antibiotic resistance in some bacteria using hydrogen sulphide (H2S).

Growing antimicrobial resistance is a major threat for the world with a projected 10 million deaths each year by 2050 if no action is taken. The World Health Organisation also warns that by 2030, drug-resistant diseases could force up to 24 million people into extreme poverty and cause catastrophic damage to the world economy.

In most bacteria studied, the production of endogenous H2S has been shown to cause antibiotic tolerance, so H2S has been speculated as a universal defence mechanism in bacteria against antibiotics.

A team at SMART's Antimicrobial Resistance (AMR) Interdisciplinary Research Group (IRG) tested that theory by adding H2S releasing compounds to Acinetobacter baumannii -- a pathogenic bacteria that does not produce H2S on its own. They found that rather than causing antibiotic tolerance, exogenous H2S sensitised the A. baumannii to multiple antibiotic classes. It was even able to reverse acquired resistance in A. baumannii to gentamicin, a very common antibiotic used to treat several types of infections.

The results of their study, supported by the Singapore National Medical Research Council's Young Investigator Grant, are discussed in a paper titled "Hydrogen sulfide sensitizes Acinetobacter baumannii to killing by antibiotics" published in the journal Frontiers in Microbiology.

"Until now, hydrogen sulfide was regarded as a universal bacterial defense against antibiotics," says Dr Wilfried Moreira, the corresponding author of the paper and Principal Investigator at SMART's AMR IRG. "This is a very exciting discovery because we are the first to show that H2S can, in fact, improve sensitivity to antibiotics and even reverse antibiotic resistance in bacteria that do not naturally produce the agent."

While the study focused on the effects of exogenous H2S on A. baumannii, the scientists believe the results will be mimicked in all bacteria that do not naturally produce H2S.

"Acinetobacter baumannii is a critically important antibiotic-resistant pathogen that poses a huge threat to human health," says Say Yong Ng, lead author of the paper and Laboratory Technologist at SMART AMR. "Our research has found a way to make the deadly bacteria and others like it more sensitive to antibiotics, and can provide a breakthrough in treating many drug-resistant infections."

Read more at Science Daily

Compounds show promise in search for tuberculosis antibiotics

Compounds tested for their potential as antibiotics have demonstrated promising activity against one of the deadliest infectious diseases -- tuberculosis (TB).

Researchers from the John Innes Centre evaluated two compounds with antibacterial properties, which had been produced by the company Redx Pharma as antibiotic candidates, particularly against TB.

TB, which is caused by the bacterium Mycobacterium tuberculosis, is often thought of as a disease of the past. But in recent years it has been increasing due, in part, to rising resistance to treatments and decreasing efficacy of vaccines.

One strategy in the search for new treatments is to find compounds that exploit well-known existing targets for drugs such as the bacterial enzyme DNA gyrase. This member of the DNA topoisomerase family of enzymes is required for bacterial DNA functionality, so compounds that inhibit its activity are much sought after as antibiotic candidates.

Using X-ray crystallography, the team elucidated the molecular details of the action of the compounds against their target.

Surprisingly, a very common mutation in DNA gyrase that causes bacteria to be resistant to a related group of antibiotics, the aminocoumarins, did not lead to resistance to the compounds under scrutiny here.

"We hope that companies and academic groups working to develop new antibiotics will find this study useful. It opens the way for further synthesis and investigation of compounds that interact with this target," says Professor Tony Maxwell one of the authors of the study which appears in the Journal of Antimicrobial Chemotherapy.

To date, efforts to develop new treatments for TB have been unsuccessful, with current treatments having been used for over 50 years.

World Health Organisation (WHO) figures reveal that each day over 4000 people die from TB and 300,000 people fall ill from the disease. Nearly 500,000 people fell ill with drug-resistant TB in 2018.

Read more at Science Daily

Bird droppings carry risk of antibiotic resistance

Bird droppings may pose more health risks than people realize, according to Rice University environmental engineers who study antibiotic resistance.

Their study found high levels of genes that encode antibiotic resistance harbored by opportunistic pathogens in the droppings of common urban ducks, crows and gulls.

The study led by postdoctoral research associate Pingfeng Yu of Rice's Brown School of Engineering appears in the Elsevier journal Environmental Pollution. Yu is a member of the lab of civil and environmental engineer and co-author Pedro Alvarez.

Previous studies determined bird-carried antibiotic resistant genes (ARGs) and bacteria (ARBs) can be transferred to humans through swimming, contact with feces or impacted soil or inhalation of aerosolized fecal particles. Studies have also analyzed bird feces found near ARG hotspots like wastewater treatment plants and drainage from poultry farms.

But the Rice study digs deeper to quantify the abundance, diversity and seasonal persistence of ARGs.

"We still do not fully understand what factors exert selective pressure for the occurrence of ARGs in the gastrointestinal system of wild urban birds," Alvarez said. "Residual antibiotics that are incidentally assimilated during foraging is likely one of these factors, but further research is needed to discern the importance of other potential etiological factors, such as bird diet, age, gut microbiome structure and other stressors."

The team that included lead authors Huiru Zhao, a student at Nankai University in China, and Rice graduate student Ruonan Sun compared "freshly deposited" samples from each species found around Houston during the winter and summer months to samples from poultry and livestock known to carry some of the same mutations.

They found that ARGs in all of the species, regardless of season, encoded significant resistance to tetracycline, beta-lactam and sulfonamide antibiotics. The researchers were surprised to see the relatively high abundance of ARGs were comparable to those found in the fresh feces of poultry occasionally fed with antibiotics.

They also found intI1, an integron that facilitates rapid bacterial acquisition of antibiotic resistance, was five times more abundant in the birds than in farm animals.

"Our results indicate that urban wild birds are an overlooked but potentially important reservoir of antimicrobial resistance genes, although their significance as vectors for direct transmission of resistant infections is possible but improbable due to low frequency of human contact," Alvarez said.

The team also looked for ARGs in soil up to 1 inch deep around bird deposits and discovered they are "moderately persistent" in the environment, with half-lives of up to 11.1 days.

Of the three species, crows showed a significantly lower level of ARGs during the summer compared to ducks and gulls, they reported.

"That's probably due to differences in their ecological niches, foraging patterns and gut microbiome," Sun said. "Crows are omnivores and feed on abundant natural food with less anthropogenic contaminations in the summer. In addition, the composition of their gut microbiome impacts ARG dissemination and enrichment in vivo, and therefore influences ARG levels in the excreted bird feces."

The researchers found that opportunistic pathogens including bacteria that cause urinary tract infections, sepsis and respiratory infections were common in the feces of all of the birds, and another associated with food poisoning was detected in samples collected during the winter.

Winter feces, they wrote, contained more of the bad bacteria that may also harbor ARGs, possibly due to lower sunlight inactivation and differences in moisture levels and temperature.

Read more at Science Daily

Bacterial enzyme could become a new target for antibiotics

MIT and Harvard University chemists have discovered the structure of an unusual bacterial enzyme that can break down an amino acid found in collagen, which is the most abundant protein in the human body.

The enzyme, known as hydroxy-L-proline dehydratase (HypD), has been found in a few hundred species of bacteria that live in the human gut, including Clostridioides difficile. The enzyme performs a novel chemical reaction that dismantles hydroxy-L-proline, the molecule that gives collagen its tough, triple-helix structure.

Now that researchers know the structure of the enzyme, they can try to develop drugs that inhibit it. Such a drug could be useful in treating C. difficile infections, which are resistant to many existing antibiotics.

"This is very exciting because this enzyme doesn't exist in humans, so it could be a potential target," says Catherine Drennan, an MIT professor of chemistry and biology and a Howard Hughes Medical Institute Investigator. "If you could potentially inhibit that enzyme, that could be a unique antibiotic."

Drennan and Emily Balskus, a professor of chemistry and chemical biology at Harvard University, are the senior authors of the study, which appears today in the journal eLife. MIT graduate student Lindsey Backman and former Harvard graduate student Yolanda Huang are the lead authors of the study.

A difficult reaction

The HypD enzyme is part of a large family of proteins called glycyl radical enzymes. These enzymes work in an unusual way, by converting a molecule of glycine, the simplest amino acid, into a radical -- a molecule that has one unpaired electron. Because radicals are very unstable and reactive, they can be used as cofactors, which are molecules that help drive a chemical reaction that would otherwise be difficult to perform.

These enzymes work best in environments that don't have a lot of oxygen, such as the human gut. The Human Microbiome Project, which has sequenced thousands of bacterial genes from species found in the human gut, has yielded several different types of glycyl radical enzymes, including HypD.

In a previous study, Balskus and researchers at the Broad Institute of MIT and Harvard discovered that HypD can break down hydroxy-L-proline into a precursor of proline, one of the essential amino acids, by removing the hydroxy modification as a molecule of water. These bacteria can ultimately use proline to generate ATP, a molecule that cells use to store energy, through a process called amino acid fermentation.

HypD has been found in about 360 species of bacteria that live in the human gut, and in this study, Drennan and her colleagues used X-ray crystallography to analyze the structure of the version of HypD found in C. difficile. In 2011, this species of bacteria was responsible for about half a million infections and 29,000 deaths in the United States.

The researchers were able to determine which region of the protein forms the enzyme's "active site," which is where the reaction occurs. Once hydroxy-L-proline binds to the active site, a nearby glycine molecule forms a glycyl radical that can pass that radical onto the hydroxy-L-proline, leading to the elimination of the hydroxy group.

Removing a hydroxy group is usually a difficult reaction that requires a large input of energy.

"By transferring a radical to hydroxy-L-proline, it lowers the energetic barrier and allows for that reaction to occur pretty rapidly," Backman says. "There's no other known enzyme that can perform this kind of chemistry."

New drug target

It appears that once bacteria perform this reaction, they divert proline into their own metabolic pathways to help them grow. Therefore, blocking this enzyme could slow down the bacteria's growth. This could be an advantage in controlling C. difficile, which often exists in small numbers in the human gut but can cause illness if the population becomes too large. This sometimes occurs after antibiotic treatment that wipes out other species and allows C. difficile to proliferate.

"C. difficile can be in your gut without causing problems -- it's when you have too much of it compared to other bacteria that it becomes more problematic," Drennan says. "So, the idea is that by targeting this enzyme, you could limit the resources of C. difficile, without necessarily killing it."

The researchers now hope to begin designing drug candidates that could inhibit HypD, by targeting the elements of the protein structure that appear to be the most important in carrying out its function.

Read more at Science Daily

Antibiotics discovered that kill bacteria in a new way

Lab technician holding a Petri dish.

A new group of antibiotics with a unique approach to attacking bacteria has been discovered, making it a promising clinical candidate in the fight against antimicrobial resistance.

The newly-found corbomycin and the lesser-known complestatin have a never-before-seen way to kill bacteria, which is achieved by blocking the function of the bacterial cell wall. The discovery comes from a family of antibiotics called glycopeptides that are produced by soil bacteria.

The researchers also demonstrated in mice that these new antibiotics can block infections caused by the drug resistant Staphylococcus aureus which is a group of bacteria that can cause many serious infections.

The findings were published in Nature today.

"Bacteria have a wall around the outside of their cells that gives them shape and is a source of strength," said study first author Beth Culp, a PhD candidate in biochemistry and biomedical sciences at McMaster.

"Antibiotics like penicillin kill bacteria by preventing building of the wall, but the antibiotics that we found actually work by doing the opposite -- they prevent the wall from being broken down. This is critical for cell to divide.

"In order for a cell to grow, it has to divide and expand. If you completely block the breakdown of the wall, it is like it is trapped in a prison, and can't expand or grow."

Looking at the family tree of known members of the glycopeptides, researchers studied the genes of those lacking known resistance mechanisms, with the idea they might be an antibiotic demonstrating a different way to attack bacteria.

"We hypothesized that if the genes that made these antibiotics were different, maybe the way they killed the bacteria was also different," said Culp.

The group confirmed that the bacterial wall was the site of action of these new antibiotics using cell imaging techniques in collaboration with Yves Brun and his team from the Université de Montréal.

Culp said: "This approach can be applied to other antibiotics and help us discover new ones with different mechanisms of action. We found one completely new antibiotic in this study, but since then, we've found a few others in the same family that have this same new mechanism."

Read more at Science Daily

The nature of salmonella is changing -- and it's meaner

Salmonella is acting up in Michigan, and it could be a model for what's happening in other states, according to a new Michigan State University study.

The study, appearing in Frontiers in Medicine, documents a substantial uptick in antibiotic resistant strains, and consequently, longer hospital stays as doctors work to treat the increasing virulent pathogens.

"If you get a salmonella infection that is resistant to antibiotics today, you are more likely to be hospitalized longer, and it will take you longer to recover," said Shannon Manning, MSU Foundation professor in the Department of Microbiology and Molecular Genetics and senior author of the study. "We need better detection methods at the clinical level to identify resistant pathogens earlier so we can treat them with the right drugs the first time."

Losing a day or more to misdiagnosis or improper treatment allows symptoms to get worse. Doctors might kill off a subpopulation of bacteria that are susceptible, but the ones that are resistant grow stronger, she added.

Salmonella is a diverse group of bacterial pathogens that causes foodborne infections. Infected patients often develop diarrhea, nausea, vomiting and abdominal pain, though some infections are more severe and can be life threatening.

When it comes to treatments, each strain reacts differently to the range of antibiotics available for prescription by doctors. So getting it right the first time is crucial.

Specifically in Michigan, doctors are seeing more strains that are resistant to ampicillin, a common antibiotic prescribed to treat salmonella. Multidrug resistance, or resistance to more than three classes of antibiotics, has also increased in Michigan and could further complicate patient treatment plans.

"We're still uncertain as to why this is happening; it could be that these antibiotics have been overprescribed in human and veterinary medicine and that possessing genes for resistance has allowed these bacteria to grow and thrive in the presence of antibiotics," Manning said. "Each state has its own antibiotic-resistance issues. It's important that the medical profession remains vigilant to ever-changing patterns of resistance in salmonella and other foodborne pathogens, rather than look for a blanket national solution."

Historically, salmonella has affected young children and the elderly, but now there's been a rise in adult cases, suggesting that the epidemiology of the infections has changed in Michigan.

Diving into individual strains of salmonella, the team of scientists found that patients with Typhimurium were more likely to have resistant infections as were patients infected during the fall, winter or spring months.

Another distinction was revealed between the strains affecting people living in rural and urban areas. Enteritis infections tend to be higher in rural areas. This may be attributed to rural residents' exposure to farm animals or untreated sources of water.

Each state's salmonella population has its own personality; so every state's approach to identifying disease drivers and effective treatments should be modified to reflect these traits.

Read more at Science Daily