The rise in untreatable bacterial infections is one of the top 10 health threats currently facing humanity. In the first of a three-part series, we discover how the Earlham Institute is tackling this existential threat.
It’s been less than a century since the discovery of penicillin started a golden age of healthcare. Plentiful antibiotics mean once-fatal illnesses are now easily treatable and previously high-risk operations have become routine.
But this era of ease is coming to an end. The overuse - and unnecessary use - of antibiotics means we are facing the prospect of a future without them.
Bacteria are rapidly becoming immune to our current arsenal of drugs. New antimicrobials have so far fallen short in countering resistance and, unless we change the way we use these drugs, any effective medicines will likely find themselves with a limited shelf life.
To gain the upper hand in this evolutionary arms race, we need the research and technology to understand and predict the emergence of new resistance genes before they arise.
A 2022 paper from Murray et al estimated that, in 2019, the emergence of anti-microbial resistance (AMR) was associated with 4.95 million deaths worldwide and considered directly responsible for an estimated 1.27 million – nearly twice the number of people killed by HIV and AIDS.
This makes antibiotic resistance one of the biggest threats to our global health and food security – the World Health Organisation (WHO) has declared AMR one of the top 10 health threats facing humanity.
One of the most deadly bugs is non-typhoidal Salmonella, estimated to cause 77,000 deaths a year. New strains containing multi-drug resistant genes have emerged all over the world during the last decade, causing an alarming spike in mortality.
Over the last four years,Professor Neil Hall, Director of the Earlham Institute, has been co-leading the 10,000 Salmonella Genomes project with the University of Liverpool. The project has yielded crucial research insights into the genetics of Salmonella and its impact on human health.
“The 10,000 Salmonella Genomes project brings together researchers and data from more than 50 countries,” explains Professor Hall, “which allows us to analyse a diverse collection of clinical and environmental Salmonella samples.”
Approximately 80 per cent of the samples come from African and Latin-American collections, both regions which are particularly at risk from AMR.
The Earlham Institute’s biology expertise, genomics platforms, and high-performance computing capabilities mean genome sequences are now available for Salmonella isolates from across the world - some of which are decades old.
This wealth of data opens the door for researchers globally to take a more detailed look at how AMR is emerging in Salmonella - including here at the Earlham Institute.
In parallel to the 10,000 Salmonella Genomes project, Professor Hall has led research focusing on how antibiotics in the environment affect the emergence of AMR in Salmonella. A brand-new sequencing approach for bacterial genomes was developed by the Earlham Institute specifically to study this.
Previously, genetic changes in bacteria were analysed either by bulk sequencing - taking an average from a very large quantity of cells - or laboriously isolating and characterising individual bacteria.
“There is a good analogy: if your head is on fire and your feet are in a freezer then, on average, you are fine,” says Professor Hall. “Averages do not give a high-resolution picture.
“And we have almost the opposite issue when we isolate a single cell - we have a clear picture of one bacterium, but we don’t know how representative that bacterium is. We could be seeing 90 per cent of the billions of cells in the culture, or one per cent.”
What was needed was the clarity of analysis from isolation combined with the large amount of data from a bulk culture. In other words, a system which was capable of producing a large quantity of single genomes at very high resolution.
This system – high-throughput single cell sequencing of whole genomes – has now been developed by the Institute and offers an unparalleled insight into evolution and diversity of Salmonella.
It gives crucial information about drug resistance and virulence factors - data which can be used to inform public health control strategies across the world.
We have almost the opposite issue when we isolate a single cell - we have a clear picture of one bacterium, but we don’t know how representative that bacterium is. We could be seeing 90 per cent of the billions of cells in the culture, or one per cent.
An antimicrobial agent is a substance which kills or limits the growth of microorganisms. These agents are not limited to antibiotics – for example, bleach, ethanol, ultraviolet light and heat all kill micro-organisms - but many are also toxic to both humans and animals.
Antibiotics specifically kill or limit bacteria without the broad-spectrum toxic effects. But, because antibiotics disrupt bacteria, they also put a selective pressure on the microbes to evolve resistance.
An organism able to shrug off an attack from an antibiotic has a significant advantage, meaning resistance-conferring mutations in the DNA spread through the population very quickly.
An experiment in collaboration with the Quadram Institute was conducted to observe the evolution of resistance in real time. Populations of Salmonella were exposed to weak levels of antibiotics and compared to a control population exposed to no antibiotics.
Populations were sampled before exposure to antibiotics and then again 14 days after exposure. Levels of resistance were compared, showing higher levels in the populations exposed to weak antibiotics.
Due to overuse throughout medicine and agriculture, weak levels of antibiotics can now be found in many ecosystems.
The study shows the constant presence of a low level of antibiotics in the environment is encouraging bacteria to develop resistance.
They were also found to develop genetic diversity much more quickly in the population - which increases the likelihood of resistance to other threats including other antibiotics.
“Antibiotics do not enter the environment at high concentrations,” says Professor Hall. “They might, for example, enter rivers through runoff from farms and become highly diluted. This would expose microbes in the environment to low levels.“
A lower dose of an antimicrobial is less likely to kill a microorganism and gives them more of a chance to evolve.
A follow-up study is currently being performed, which will follow Salmonella cultures over a month. Three cultures will be exposed to different levels of antibiotics and their genomes will be compared to a culture allowed to grow without antibiotic exposure.
One culture will be exposed to strong antibiotic treatment, another will be exposed to weak treatment, and a third will be given pulsed exposure - a strong dose, followed by a period with no antibiotics, followed by another dose. This is designed to mimic effects of antibiotics entering the general environment.
Studies mimicking antibiotic exposure are a widespread critical tool in the fight against AMR. They can help us understand the evolution, rise and spread of resistance genes. The Earlham Institute’s single cell genomic method provides a new higher-resolution understanding of how a population of cells responds to this treatment.
In our next feature, Technical Development Group Leader, Dr Iain Macaulay, will explain the challenges of developing the single cell isolation system.
