Dubbed the ‘slow-moving pandemic’, antimicrobial resistance (AMR) is one of the greatest global threats to health. By 2050, the UN predicts that AMR will be the cause of 10 million deaths every year. Overuse and inappropriate prescribing of antimicrobials have led to the evolution of resistance in many pathogens – and with just a single new antimicrobial discovered in the last 36 years, available treatment options are limited.

Without effective antimicrobials, even just a scratch can kill, and we’d return to an era where childbirth is a life-threatening event. Simple wound infections could become fatal without treatments for the common environmental bacteria we encounter every day.  This threat is increased by the growing number of surgeries associated with an ageing population, with mortality rates for routine operations such as hip and knee replacements set to rise as we begin to run out of effective antimicrobials.

As the threat posed by AMR looms, genomic research is going to be essential in improving our understanding of how resistance evolves and spreads, and its modes of action. By gaining a deeper insight into the genetic changes underlying resistance, researchers will have a better chance of developing new and more efficacious antimicrobials, controlling the spread of resistance and protecting future populations.

Microorganisms such as bacteria, viruses and fungi evolve and mutate at a much faster rate than humans. These genetic changes mean microorganisms adapt rapidly to environmental stressors, and traits that favour their survival – such as resistance to antimicrobials – become dominant. As a result, the useable lifespan of antimicrobials is relatively short, as the more frequently antimicrobials are used, the more resistant microorganisms remain in the population, thriving and reproducing.

Bacteria also come with the unique additional challenge of ‘horizontal transmission’, whereby the genes that hold resistant traits are passed from one bacteria to another on transmissible genetic elements called plasmids. These plasmids could hold the genetic sequence for a protein that breaks down an antibiotic, for example. This type of resistance is particularly dangerous because it means that just one resistant bacterium can confer this trait to all the bacteria in the local area, which can have devastating outcomes, particularly in healthcare settings.

To develop solutions to AMR, knowing which genes lead to resistance, their mode of action and where they reside on the genome is extremely important. Building a deep insight into the bacterial genome and identifying which genes confer resistance is key to understanding how they work, whether resistance is likely to emerge in other bacterial species and which other antibiotics may also be affected when similar mutations occur.

‘Dubbed the ‘slow-moving pandemic’, antimicrobial resistance is one of the greatest global threats to health and by 2050, the UN predicts that AMR will be the cause of 10 million deaths every year’

Even just one change in a bacterial genome can render an antibiotic ineffective, but often resistance emerges because of several mutations, leading to a structural change in the bacteria. These mutations could also affect the physical features of the microorganism and influence virulence, pathogenicity or environmental outcomes.

Given the complex genetic factors underlying resistance, a deep and comprehensive insight into the genome is essential in tackling AMR. Researchers are working on constructing reference genomes for many important microbial species, and next-generation sequencing has already proven critical in this endeavour. But to fully understand the genetic drivers of resistance, it is vital that reference genomes are built on a strong foundation.

To build that strong foundation, researchers are increasingly using genomic technologies to explore microbial genomes. Until recently, short-read sequencing has been the preferred technology when sequencing microbial genomes, but genomes built using this short-read data come with disadvantages – especially when plasmids are also involved. Stitching together multiple genome fragments generated by short-read sequencing leads to gaps and mistakes and makes it challenging to get a complete view of the bacterial genome. This can mean that AMR or transmission chains are not correctly characterised, hindering the understanding and discovery of new antimicrobials.

To overcome these issues and build better draft genomes, researchers are turning to long-read whole genome sequencing (WGS). While this technology was previously only used during disease outbreaks and in lab settings, improved accessibility and advances in long-read sequencing technology means we are now seeing WGS used more often in clinical settings. Developments in long-read sequencing technologies mean complete microbial genomes can be sequenced more quickly, at a higher throughput and for a lower cost. Long-read sequencing gives a complete picture of the whole microbial genome while removing the guesswork that comes with stitching together short-reads.  This provides an extra layer of insight and confidence in the characterised genomes produced – answering important questions like ‘what is it?’, ‘how is it spreading?’, ‘how aggressive is it?’ and ‘is a strain localised or is it spreading within the community?’.

In a clinical setting, an outbreak of resistant bacteria can be very serious and costly. Genomic data can support doctors in choosing antimicrobials that will treat the target infection effectively. In countries where bacteria resistant to several types of antibiotics – also known as multi-drug resistant (MDR) bacteria – are more prevalent, hospitals are increasingly turning to a surveillance method of infection control rather than a reactive approach.

Hospitals are now using long-read sequencing for proactive, continuous infection surveillance for common hospital pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and Clostridium difficile. Originally tracked with strain typing methods such as pulsed-field gel electrophoresis (PFGE), protein typing and sequence typing, long-read sequencing offers a higher resolution and can capture genetic changes that lead to alteration or loss of typing elements. The detail and accuracy offered by long-reads means that the evolution and spread of an outbreak can be better understood and intervention can be implemented to protect patients.

When outbreaks occur, it is vital to collect information at scale and quickly. By building and maintaining private and public databases on microbial genomes, scientists can leverage the information they have to launch the most effective response. As resistance continues to rise and treatment options dwindle, a full view will be key to tackling outbreaks of known pathogens and figuring out the best way to tackle any novel pathogens that arise.

To fully get a handle on AMR, it is important that managing existing outbreaks takes place alongside research and development. The clock is ticking for the antimicrobial therapies currently in use around the world and the spread of resistance is not slowing down. With the last new antibiotic approved for clinical use being discovered in 1987, there is growing pressure to discover new therapies.

‘Overuse and inappropriate prescribing of antimicrobials have led to the evolution of resistance in many pathogens – and with just a single new antimicrobial discovered in the last 36 years, available treatment options are limited’

In drug discovery, scientists need genomic-level insight to accelerate the discovery of new antimicrobial therapies. To know how to best treat an infection, a deep understanding of microbial structure and mode of action is needed to identify drug targets. It’s also important to understand which areas of the genome are more or less likely to change, as a drug targeting a highly mutable area may quickly become ineffective as resistance evolves.

Just this year, researchers were able to leverage genomics insights to develop an antibiotic that binds to a protein that cannot mutate – meaning there is limited possibility of resistance arising in this bacterial population. This new development relied on a whole genome sequence of the target bacteria to determine which areas of the genome were necessary for bacterial survival and then identify compounds that are able to target these areas. While the drug is yet to be commercialised and approved for use, the work underlines the criticality of genomic data in tackling AMR.

As the fight against AMR continues, long-read sequencing technologies are an important tool in our arsenal. With whole genome sequencing being faster, more accessible and more accurate than ever before, we now have the best data available to get a handle on AMR. By collaborating and sharing data on drug-resistant bacteria, there is hope for new antimicrobial therapies, better control and surveillance strategies, and the opportunity to predict outbreaks and respond proactively to minimise the impact. To realise the potential of genomics in reversing AMR, it is key that the data underpinning discoveries is accurate and delivers a complete picture of how micro-organisms work.

Neil Ward is Vice President and General Manager for Europe, Middle East and Africa at PacBio