What does the future hold? Improved detection, treatment and management of One Health AMR

A multitude of studies, reports and strategy documents from academics, not-for-profits, government agencies and industry have highlighted the threat that antimicrobial resistance (AMR) poses to the global economy and human health. New antimicrobial drugs are needed, and new sustainable solutions will potentiate how long these new drugs will be effective. The problems created by AMR are clear and, although more epidemiology and surveillance studies may help to define the parameters of the problem, until they are conducted with clear goals for intervention, they will not directly generate solutions. How are we most likely to find ways to effectively combat AMR in the coming decade? In this article, three Australian research initiatives focused on AMR provide their views.

A view from the Centre to Impact AMR

Recognising that in the next 10 years there will be new antimicrobial drugs brought onto the global market, the Centre to Impact AMR was established in January 2020 to bring together the disciplines and research pathways required to protect the efficacy of both current and future drugs. Beyond simple stewardship, the Centre is highlighting and developing sustainable solutions to the AMR problem. These solutions range from stopping the use of antimicrobials in soaps and detergents, to phage control of specific bacterial superbugs, to surveillance programs that focus on incorporating interventions instead of just being look-see studies, to preventative vaccination. Importantly, genuine sustainable solutions that have long-term impact go beyond biotech developments of a new drug. Viewed with a One Health lens, the problems caused by AMR can only be understood by transdisciplinary approaches and can only be addressed with changes that will deliver outcomes at local, state, national and regional levels. Both components are hard to achieve, but AMR is a wicked problem and real solutions with lasting effects are going to be difficult to implement.

Why tackle something so challenging? The cost to human health and well-being is huge. There is a consensus use of a figure of ~10 million deaths every year due to AMR infections being a reality by 2050.¹ In fact, we may well be there already given that nearly 5 million AMR-associated deaths were identified in 2019,² a figure that will include tens of thousands of Australians every year. Three points are worth appreciating here.

First, deaths associated with AMR are almost always deaths caused by AMR, as many deaths are attributed to an underlying disease rather than the acute infection causing death, such as the cancer patients whose successful surgeries were negated by being killed by a superbug infection, the women whose successful Caesarean surgery was followed by being killed by a superbug infection, the cystic fibrosis patients who recovered after a successful lung transplant but were then killed by a superbug infection.

Second, it is becoming apparent that an increasing proportion of the people going into hospitals now carry AMR superbugs on them (in their skin microbiomes) or in them (in their lung and gut microbiomes). Thus, personal choices – such as constant use of soaps containing antimicrobials promoted by industry marketing – have an increasingly important role in what will happen when cuts, scrapes or medical procedures introduce those superbugs into deeper tissues.

Third, our region of the world has the countries least affected by AMR (Australia and New Zealand) as well as countries ranked among those most affected by AMR (e.g. China, India). It is therefore incumbent upon us to work with partners throughout the Indo-Pacific region to share knowledge and sustainable solutions across the region, in addition to supporting equitable access to any new drugs and better antimicrobial stewardship practices. The Australian federal government’s Indo-Pacific Centre for Health Security has AMR as a high priority, and the Indo-Pacific Alliance Against AMR (see https://indopacifichealthsecurity.dfat.gov.au/the-centre) is an emergent response to this issue driven through academic institutions with shared intent.

A view from CEAStAR

The Australian Research Council (ARC) Industrial Transformation Training Centre, CEAStAR (the Centre for Environmental and Agricultural Solutions to Antimicrobial Resistance, see www.ceastar.org.au), was established in July 2023 to train the next generation of researchers needed to combat the inexorable rise of AMR. As highlighted in a recent report from the AMR Industry Alliance,³ the exit of antibiotic researchers from major pharmaceutical companies over the past decades means that most new antimicrobial development stems from small startups and academic labs, with as few as 2000–3000 antimicrobial researchers remaining worldwide. A key focus of CEAStAR, a collaboration between two universities (The University of Queensland and The University of Adelaide) and seven industry partners (BiomeMega, Calix, Edenvale, Invion, Lixa, MGI Australia, Neoculi) is to ensure that the skills needed to test and develop new antimicrobial agents are not lost. The 12 PhD students and 5 postdoctoral fellows funded by CEAStAR will work on a range of industry-driven projects, and all will initially complete a training ‘boot camp’ that will impart fundamental microbiology and drug discovery skills. CEAStAR will provide additional ongoing training opportunities that are also available to researchers from the industry partners and other entities. CEAStAR views public engagement and education as essential for improving future efforts to combat AMR and will be developing a number of initiatives to deliver on this goal.

The projects proposed by CEAStAR’s partner organisations effectively provide a view into a crystal ball from an industry perspective – reflecting their priorities for agricultural and environmental solutions for AMR over the next 10 years, a timeframe in which products will hopefully make it to market. Notably, for those developing new treatments for infected animals, only one of the partners is developing what could be considered a ‘traditional’ small molecule antimicrobial agent. Project products include a photoactivated therapy, an antibiotic potentiator that disrupts biofilms, and two non-conventional antimicrobial treatments – with one based on inorganic MgO and other on wine production byproducts. Microbiome modulation through probiotic administration, and metagenomic microbiome and environmental analysis complete the diverse set of company interests. The latter two projects highlight the importance in being able to improve our detection of AMR, as well as treat it. It is striking that the focus on many of these projects mirrors the shift that has been seen in the development of human antimicrobial treatments, which now include a range of non-traditional approaches, including potentiators and probiotic therapies.^4,5 The need for these alternative approaches is particularly important in an agricultural context, with an imperative that new antibiotics developed for livestock treatment do not overlap with equivalent human therapeutics, in order to reduce the potential transmission of resistance mechanisms across the One Health sectors.

A view from CO-ADD

The Community for Open Antimicrobial Drug Discovery (CO-ADD, see https://www.co-add.org/) is a ‘crowd-sourcing’ initiative established in 2015 to kick-start the discovery of new antibiotics.⁶ Initially supported through strategic funding from the Wellcome Trust, The University of Queensland and from the university’s Institute for Molecular Bioscience, CO-ADD was designed to fill an identified gap: synthetic chemists had made a range of unique molecules with unusual structures, but most were never tested for antimicrobial activity due to the difficulty in accessing testing services or a lack of interest in assessing biological activity. CO-ADD provides free, unencumbered testing against five bacteria and two fungi, with results sent back to the collaborator on the condition that, within 2 years, compound structures and associated microbial activity would be made available in a public database. The long-term strategy behind this database component reflects CO-ADD’s vision of future antibiotic discovery: artificial intelligence (AI) and machine learning (ML) will play a critical role in the next decade. Several recent publications highlight the potential of this approach.^7–10 However, the ‘garbage in, garbage out’ rule applies. Without carefully curated datasets of compound structures tested in assays under standardised conditions, developing accurate predictions of structure–activity relationships is impossible. CO-ADD has now tested over 350,000 diverse compounds submitted by over 350 research groups in 45 countries,⁶ and is populating a public database (see http://db.co-add.org/) with the results. Although AI and ML analyses and predictive models derived from the CO-ADD dataset are yet to be published, the potential value of the database is indicated by a study that identified metal complexes had more than 10-fold higher chance of being active compared to traditional ‘organic’ compounds, without any greater general toxicity.¹¹

Conclusions

It is clear that AMR is one of the most challenging problems facing society, and that ‘more of the same’ is not a sustainable approach to deliver effective solutions. The ubiquitous presence of microorganisms that are intermingled across all aspects of human existence, including the environment, livestock and plant-based agriculture, companion animals and humans themselves means that future solutions must take a holistic approach, where outcomes and efficacy are assessed across all sectors. As we move forward through the 21st Century, with multiple centres and organisations focussed on solutions to AMR emerging across Australia, coupled with the success we have had until now in suppressing the effects of AMR in Australia,² there is a promise of significant beneficial impact here on the multifaceted problem of AMR.