AMR: why we need to advance the discovery of new antimicrobials

World Antimicrobial Awareness Week highlights the fact that antimicrobials have formed the bedrock of modern medicine, making surgeries, cancer care and treatments for life-threatening infections possible and improving human health in the process. 

For years now, experts have laboured against the rise of antimicrobial resistance (AMR), urging governments to put in place policies that promote R&D into new antibiotics and to change the financial systems for how antibiotics are currently sold.  

The theme for this year’s World Antimicrobial Awareness Week is ‘Preventing antimicrobial resistance together,’; a bold objective and one that calls into question our progress against curbing AMR. Here, DDW Editor Reece Armstrong looks at the current state of drug resistance and what’s been happening within pharma to curb this threat.

So where are we? 

According to data from the World Health Organisation (WHO)1 only 17 countries have the financial provision to support their national AMR action plans. Whilst the data show that most countries are implementing or planning national AMR strategies, the fact that most countries are yet to have the financial backing for such plans highlights the difficulties’ governments are facing in this aspect. Countries that do have the financial provision for such plans include the UK, the US, Spain, Pakistan, Japan, France and a handful of others.  

The data, which come from a self-assessment tool designed to track AMR, provides a snapshot of the progress made by governments.  

In terms of monitoring for AMR, out of the total countries involved in the database, it’s almost an even split for those that have implemented a surveillance system for AMR and those who haven’t. The data show that 83 counties are yet to establish or start to implement a surveillance system for AMR whilst 81 counties have a system in place.  

The database also shows that Covid-19 had an overall negative impact on countries’ AMR strategies. Only 66 countries said that the pandemic had a positive impact on the implementation of national AMR plans, and the majority of respondents said that there was a negative operational and governance, and administrative, impact on their AMR plans.  

A study by the Centers for Disease Control and Prevention (CDC) supports this2, stating that during the pandemic, the threat of antimicrobial-resistant infections got worse with a 15% reported increase of both hospital-onset infections and deaths in the first year of Covid-19.  

The increase of hospital-onset infections contributed to the rise of AMR in US hospitals, with antibiotics being used as a first-line treatment for many patients with pneumonia-like symptoms, even though patients would have likely had Covid-19, for which antibiotics cannot treat.  

This kind of prescribing of antibiotics to conditions for which they cannot treat is a major factor in the increase of AMR. The report indicates that from March 2020 to October that year, around 80% of patients hospitalised with Covid-19 received some form of antibiotic. It states that whilst some antibiotic prescribing can be “appropriate when risks for related bacterial or fungal infections are unknown,” this level of high prescribing can “put patients at risk for side effects and create a pathway for resistance to develop and spread.”  

Michael Craig, MPP, Director of CDC’s Antibiotic Resistance Coordination & Strategy Unit said that the set back the US experienced during the pandemic “must be temporary.”  

“The Covid-19 pandemic has unmistakably shown us that antimicrobial resistance will not stop if we let down our guard; there is no time to waste. The best way to avert a pandemic caused by an antimicrobial-resistant pathogen is to identify gaps and invest in prevention to keep our nation safe,” Craig added.  

What about pharma?  

The lack of financial incentive for pharmaceutical companies developing antibiotics means that many companies no longer focus their efforts on R&D for antimicrobials. The majority of R&D focused on the development on antimicrobials comes from small-to-medium sized companies, though recent developments in the sector have saw a handful of larger pharmaceutical companies join initiatives.  

A review of the antibacterial products in preclinical development by the WHO3 shows that only 30% of research is coming from medium or large companies. The majority of R&D for AMR is coming from private institutions with micro-sized (less than 10 employees) companies accounting 37% of the work and small (11-50 employees) accounting for 33% of the work.  

Overall, the WHO’s assessment of antibacterial products in clinical development4 highlights the lack of activity in the sector, stating that the clinical pipeline and recently approved antibiotics “are insufficient to tackle the challenge of increasing emergence and spread of antimicrobial resistance.”  

Still, there are positive developments occurring within the sector. The AMR Action Fund was launched in 2020 as the largest public-private partnership investing in antimicrobials. With backing from the likes of the WHO, the European Investment Bank and pharmaceutical companies including Bayer, Amgen, Boehringer Ingelheim, Eli Lilly, GSK, Johnson & Johnson and more, the partnership aims to invest $1 billion into clinical-stage biotech companies in a bid to bring new antibiotics to market. Ultimately, the goal for the AMR Action Fund is to help bring two to four new antibiotics to market by 2030. The partnership has made its first investments into two pharmaceutical companies – Venatorx Pharmaceuticals & Adaptive Phage Therapeutics – marking the beginning of plans this year by the fund to invest $100 million in companies that are developing antimicrobials that target urgent unmet clinical needs.  

A good step then, though AMR Action Fund CEO Henry Skinner warns that the organisation alone isn’t enough to combat AMR.  

“Our investments are substantial, but we alone are not enough to take on the global challenge of AMR. It is now imperative that policymakers around the world enact market reforms to support investment in these urgently needed medications,” Skinner said.  

Going Forward 

Warnings about AMR’s impact on global healthcare have been issued for some time now. Without real change, healthcare systems are under threat from infections that were once thought to be easily treatable, and standard medical procedures could become a thing of the past. The WHO’s World Antimicrobial Awareness Week encourages a collaborative approach to the prudent use of antimicrobials and both policymakers and industry will have to work together to ensure that targets can be met and R&D is focused in the correct areas. 

Going forward, drug makers may look to the use of technology to help expedite time-to-market or to advance the discovery of new antimicrobials.  

In 2020, a team of researchers from MIT used a machine-learning platform to identify a new antibiotic compound which was shown to kill certain strains of bacteria, including resistant-bacteria. The computer model that was designed can screen over 100 million compounds in a matter of days and picks out potential antibiotics that kill bacteria using different mechanism to current drugs. 

Professor of biology and computer science at Technion (the Israel Institute of Technology) Roy Kishony called the study5 groundbreaking.  

“This groundbreaking work signifies a paradigm shift in antibiotic discovery and indeed in drug discovery more generally. Beyond in silica screens, this approach will allow using deep learning at all stages of antibiotic development, from discovery to improved efficacy and toxicity through drug modifications and medicinal chemistry,” Professor Kishony said. 

More recently, teams of researchers from the Northeastern University in Boston and Biozentrum of the University of Basel used computational analysis to discover a new antibiotic and its mode of action.  

The researchers discovered Dynobactin, an antibiotic that can kill Gram-negative bacteria, which can be responsible for causing infections such as pneumonia and bloodstream infections.

The team also discovered the mode of action of the antibiotic Darobactin and used this knowledge to integrate it into the screening process for new compounds.  The teams made use of the fact that many bacteria produce antibiotic peptides to fight each other. And these peptides are encoded in the bacterial genome.  

Since the genes for peptide antibiotics share a similar characteristic, the teams could use computational analysis to screen the entire genome of bacteria that produced such peptides.  

The new compound was found to be effective in mice with life-threatening sepsis caused by resistant bacteria, which was succesfuly treated with Dynobactin. More so, the teams hope that by combining certain chemical features of both Dynobactin and Darobactin, potential drugs could be further improved and optimised.  

Speaking about the research, Professor Sebastian Hiller from the University of Basel said: “The computer-based screening will give a new boost to the identification of urgently needed antibiotics. In the future, we want to broaden our search and investigate more peptides in terms of their suitability as antimicrobial drugs.”  

The study represents how technology is being used both within drug discovery and the fight against AMR. 

Thibault Géoui, Senior Director, Discovery Biology and Predictive Risk Management at Elsevier, agrees that technologies like AI will be essential to solving global AMR challenges.  

Recent research from Elseveir’s Scopus database points to an increase in research investigating priority pathogens related to AMR, but translating this research into marketable therapies will require time and effort. 

“Without digital technologies, such as AI, drawing on trustworthy, relevant data, this insight will remain hidden. Keeping up to date with the latest research in antimicrobials has now become beyond human capacity. We should not overlook the importance of technology in tackling these big data challenges,” Géoui told DDW. 

“Scientific research takes time, but during global disease outbreaks time is a luxury researchers can’t afford. The influx of data we see here with AMR mirrors what we saw in the early days of Covid-19 – when researchers were scrambling to produce and share data as quickly as possible. During the pandemic we saw researchers begin to use cutting-edge methods such as NLP and advanced analytics to incorporate the vast amounts of untapped data generated in experiments and published in scientific papers, as well as data held in high-quality (and continuously updated) databases. Such technologies enabled researchers to prioritise projects, identify ideal targets quickly, and even forecast clinical side effects. We now need to see this approach applied in the fight against AMR,” he added.  

Make no mistake though, getting new antibiotics to market is perhaps the only way out of this crisis. The Association of the British Pharmaceutical Industry (ABPI) has said that developing new antibiotics is essential to winning the fight against resistant infections.  

The ABPI says that governments and pharmaceutical companies must collaborate to both protect existing antimicrobial treatments and develop long-term solutions.  

“The UK is already playing a leading role in tackling antibiotic resistance through changes to how it incentivises and rewards antibiotic innovation, but it cannot win this fight alone. We must continue to spur global efforts to improve how we use existing antibiotics and prioritise the development of new antimicrobial treatments,” said Amit Aggarwal, Executive Director, Medical Affairs at the ABPI.   

References 

1: Global Database for Tracking Antimicrobial Resistance (AMR)
Country Self- Assessment Survey (TrACSS) 

2: https://www.cdc.gov/drugresistance/covid19.html  

3: https://www.who.int/observatories/global-observatory-on-health-research-and-development/monitoring/antibacterial-products-in-clinical-development-for-priority-pathogens  

4: https://www.who.int/observatories/global-observatory-on-health-research-and-development/monitoring/antibacterial-products-in-clinical-development-for-priority-pathogens  

 

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