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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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.

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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."

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