Evolution is not as random as previously thought

A groundbreaking study has found that evolution is not as unpredictable as previously thought, which could allow scientists to explore which genes could be useful to tackle real-world issues such as antibiotic resistance, disease and climate change.

The study, which is published in the Proceedings of the National Academy of Sciences (PNAS), challenges the long-standing belief about the unpredictability of evolution, and has found that the evolutionary trajectory of a genome may be influenced by its evolutionary history, rather than determined by numerous factors and historical accidents.

The study was led by Professor James McInerney and Dr. Alan Beavan from the School of Life Sciences at the University of Nottingham, and Dr. Maria Rosa Domingo-Sananes from Nottingham Trent University.

"The implications of this research are nothing short of revolutionary," said Professor McInerney, the lead author of the study.

"By demonstrating that evolution is not as random as we once thought, we've opened the door to an array of possibilities in synthetic biology, medicine, and environmental science."

The team carried out an analysis of the pangenome -- the complete set of genes within a given species, to answer a critical question of whether evolution is predictable or whether the evolutionary paths of genomes are dependent on their history and so not predictable today.

Using a machine learning approach known as Random Forest, along with a dataset of 2,500 complete genomes from a single bacterial species, the team carried out several hundred thousand hours of computer processing to address the question.

After feeding the data into their high-performance computer, the team first made "gene families" from each of the gene of each genome.

"In this way, we could compare like-with-like across the genomes," said Dr. Domingo-Sananes.

Once the families had been identified, the team analysed the pattern of how these families were present in some genomes and absent in others.

"We found that some gene families never turned up in a genome when a particular other gene family was already there, and on other occasions, some genes were very much dependent on a different gene family being present."

In effect, the researchers discovered an invisible ecosystem where genes can cooperate or can be in conflict with one another.

"These interactions between genes make aspects of evolution somewhat predictable and furthermore, we now have a tool that allows us to make those predictions," adds Dr. Domingo-Sananes.

Dr Beavan said: "From this work, we can begin to explore which genes "support" an antibiotic resistance gene, for example. Therefore, if we are trying to eliminate antibiotic resistance, we can target not just the focal gene, but we can also target its supporting genes.

"We can use this approach to synthesise new kinds of genetic constructs that could be used to develop new drugs or vaccines. Knowing what we now know has opened the door to a whole host of other discoveries."

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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.

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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.

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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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Novel nanoantibiotics kill bacteria without harming healthy cells

The Centers for Disease Control and Prevention estimates that more than 2.8 million Americans experience antibiotic-resistant infections each year; more than 35,000 die from those infections.

To address this critical and worldwide public health issue, a team of researchers led by Hongjun (Henry) Liang, Ph.D., from the Texas Tech University Health Sciences Center (TTUHSC) Department of Cell Physiology and Molecular Biophysics, recently investigated whether or not a series of novel nanoparticles can kill some of the pathogens that lead to human infection without affecting healthy cells.

The study, "Hydrophilic Nanoparticles that Kill Bacteria while Sparing Mammalian Cells Reveal the Antibiotic Role of Nanostructures," was published Jan. 11 by Nature Communications. Other study members of the Liang team, all from TTUHSC, included Yunjiang Jiang, Ph.D., Wan Zheng, Ph.D., Keith Tran, Elizabeth Kamilar, Jitender Bariwal, Ph.D., and Hairong Ma, Ph.D.

Past research has shown that hydrophobicity (a molecule's ability to repel water) and hydrophilicity (a molecule's ability to attract and dissolve in water) affects cells; the more hydrophobic a substance is, the more adverse the reaction it will cause. However, Liang said, there is no quantitative standard for how much hydrophobicity is acceptable.

"Basically, you can kill bacteria when you increase hydrophobicity," Liang said. "But it will also kill healthy cells, and we don't want that."

For their study, the Liang team used novel hydrophilic nanoparticles known as nanoantibiotics that were developed by Liang's laboratory. Structurally speaking, these novel nanoantibiotics resemble tiny hairy spheres, each composed of many hydrophilic polymer brushes grafted onto silica nanoparticles of different sizes.

These synthetic compounds, which Liang's lab produces, are designed to kill bacteria via membrane disruptions like antimicrobial peptides do, but through a different mode of membrane remodeling that damages bacterial membranes and not mammalian cells. Antimicrobial peptides are a diverse class of amphipathic molecules (partially hydrophilic-partially hydrophobic), which occur naturally and serve as the first line of defense for all multicellular organisms. The direct use of antimicrobial peptides as antibiotics is limited by their stability and toxicity.

There have been other studies in which researchers grafted amphipathic molecules onto nanoparticles, and they too kill bacteria. However, Liang said the primary issue in using amphipathic molecules is that it becomes very difficult to strike the right balance between their hydrophobicity and hydrophilicity so that the toxicity of these molecules to our own cells is significantly reduced.

"In our case, we remove that uncertainty from the equation because we started with a hydrophilic polymer," Liang pointed out. "The cytotoxicity of hydrophobic moieties is not a concern anymore. Those hydrophilic polymers by themselves, or the silica nanoparticles alone don't kill bacteria; they have to be grafted onto the nanostructure to be able to kill bacteria. And so, this is the first important discovery."

The Liang team also discovered that the degree of antibiotic activity is affected by the size of the hairy spheres, which according to Liang is the second important discovery of this research. Those measuring 50 nanometers and below appear to be much more active than those whose size exceeds 50 nanometers. Liang said those measuring approximately 10 nanometers appear to be the most active. (Using synchrotron small angle x-ray scattering and other methods, the Liang team is able to interpret the molecular mechanism of the size-dependent antibiotic activity.)

These discoveries are important because using nanoantibiotics to kill bacteria evades all known mechanisms of bacterial resistance unless bacteria completely revamp their pathways for making cell membranes, which Liang said is unlikely.

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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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