Antimicrobial resistance
Krzysztof Potempa
Dreamster dedicated to the prevention and treatment of mental health disorders that affect at least 1 in 6 people worldwide!
Last updated 23 February 2025
This article addresses among others: 1) tackling drug-resistant infections globally; 2) AMR: could AI be the solution? 3) the sustainable discovery and development of new antibiotics; 4) Antibiotic resistance breakers: can repurposed drugs fill the antibiotic discovery void? 5) Unrealized targets in the discovery of antibiotics for Gram-negative bacterial infections; 6) Advancing global antibiotic research, development and access; 7) Momentum builds around new antibiotic business models; 8) A community-based approach to new antibiotic discovery; 9) Bring the magic back to the bullets; 10) Confronting antimicrobial resistance 2024 to 2029 and UK 20-year vision for antimicrobial resistance.
For a great introduction see Course: Antibiotic Resistance - The Silent Tsunami – Antibiotic resistance – ReAct
"I find it incredible that doctors must still prescribe antibiotics based only on their immediate assessment of a patient’s symptoms, just like they used to when antibiotics first entered common use in the 1950s”-Jim O'Neill. In the private sector, pharmaceutical companies have divested from their antibiotics research teams steadily, to the benefit of areas that may not be ‘easier’ but that definitely have a higher commercial return. In oncology, for instance, there were close to 800 new products in the development pipeline in 2014, of which around 80 percent were potentially ‘first-in-class’ – compared to a total antibiotics pipeline today of fewer than 50 products. Moreover, the rate of new product registrations in oncology since 2010 has been twice as high as it was in the 2000s – demonstrating the impact of a significant and sustained industry focus on a scientifically challenging but commercially lucrative disease area. Antibiotics also attract a very small – and shrinking – share of venture capital funds. Of 38 billion USD venture capital invested into pharmaceutical R&D between 2003 and 2013, only 1.8 billion USD was invested into antimicrobials research, with total investments falling by more than a quarter over that period, despite the issue of drug-resistance becoming worse and, at least recently, becoming better known by the public. The same story is true in the allocation of public research funds by governments. For example, the US National Institutes of Health (NIH), the world’s largest single funder of health research, allocated just 1.2 percent of its grant funding to AMR-related research between 2009 and 2014, compared to 18.6 percent (more than five billion USD annually) to cancer research. This trend has begun to turn in some areas, with the US Government and initiatives such as the European based Joint Programming Initiative on AMR (JPIAMR) helping to channel more public funding into AMR research. Two key programmes specifically supporting antibiotic development, the US Biomedical Advanced Research & Development Agency (BARDA) Broad Spectrum Antimicrobials programme, and the European Innovative Medicines Initiative (IMI) New Drugs For Bad Bugs (ND4BB) programme, together provide direct financial support to nearly 20 percent of all antibiotics currently under development globally, and half of those targeting Gram-negative bacteria. Nonetheless, there remains much more to do to close the profound gap with funding for R&D in non-communicable diseases. Finally, this lack of investment and interest by companies and governments has in turn contributed to a decline in the attractiveness and prestige of the field. Academic careers do not reward the skills required for antibiotic discovery, where advancement and prestige is driven by publishing in journals seen as focused on ‘cutting-edge science’ – not something often associated with microbiology (11).
AMR: could artificial intelligence be the solution?
Towards the sustainable discovery and development of new antibiotics
Highlights: 1) Unfortunately, the dramatic worldwide rise of bacterial pathogens resistant to antibacterial agents cannot be counteracted by the current low development pace of therapeutics with new mode(s) of action (MoA(s)). While there are nearly 4,000 immuno- oncology agents in development, only about 30–40 new antibacterial compounds are currently in the clinical trial phases of development, and, notably, those candidates targeting World Health Organization (WHO) priority pathogens are derivatives of existing classes. 2) only a small fraction of the antibiotics approved over the past 40 years represents new compound classes, while the majority were derived from already known chemical structures, and the most recent new class of antibiotics was discovered during the 1980s. 3) Large pharmaceutical companies across the globe are extremely hesitant to fund early antibiotic R&D and, particularly, new classes of compounds, since the return on investment in this area is generally low or even negative (1)
As a result of challenges, in recent years several biotechnology companies have declared bankruptcy or exited this space, including those who had successfully developed new antimicrobials. In fact, while 15 new antimicrobials were approved over the past decade, a third of the companies behind those medicines subsequently filed for bankruptcy or exited the field (9).
There have been only 10 new antibiotics or combinations approved by stringent regulatory authorities between 2017 and 2023, only 2 of which are defined as innovative by the WHO. None are considered to constitute a new class of antibiotics (10).
Antibiotic resistance breakers: can repurposed drugs fill the antibiotic discovery void?
Highlights: 1. Priority compounds for repurposing for Gram-negative bacteria (Ciclopirox, Loperamide) (Table 1).
2. Priority compounds for repurposing for Gram-positive bacteria (Berberine).
3. Priority compounds for repurposing for both Gram-negative and Gram-positive bacteria (Curcumin, Epigallocatechin?3?gallate (EGCG), (+)-Naltrexone and (+)-Naloxone).
4. Some drugs such as aspirin, diclofenac, ibuprofen, ivermectin, lauric acid or monolaurin, metformin, and vitamin D3 were excluded owing to a lack of compelling evidence, although future research could identify these drugs as potential ARBs (Table 3) (2)
Unrealized targets in the discovery of antibiotics for Gram-negative bacterial infections
Highlights: 1) With the emergence of genomics-driven strategies more than 20 years ago, antibacterial discovery became target oriented, and traditional phenotypic screening of compound libraries of synthetic and natural product origins was largely abandoned (6). However, massive industry efforts from companies including GlaxoSmithKline and AstraZeneca, involving close to 200 high-throughput screening programmes with 60–70 different approaches and targets, did not result in a development candidate with a broad spectrum of activity, despite using the newest genomic knowledge and technologies of their time.
2) Despite the high number of targets described in diverse publications and other resources with overly optimistic or incomplete validation, the prioritization and choice of the most promising targets for subsequent drug discovery programmes are challenging.
领英推荐
3) The minimum criteria for an antibacterial target are that it should be essential to bacterial survival, conserved across all species of interest, accessible to inhibitors and capable of binding to drug-like compounds (that is, ‘druggable’). There should also be evidence that selective inhibition is possible against any human homologue to ensure an acceptable safety profile (Table 1 and Box 1), and it is important to consider the potential for the development of target-based drug resistance (3).
Advancing global antibiotic research, development and access
Highlights: 1) With about 80% of researchers who were active in antibiotic research & development now working in other fields, there is a worrying diminishingly small number of experts in antibiotic R&D.
2) Since 2022, the AMR Action Fund has invested in six companies carrying out clinical trials of antibacterials for priority pathogens. The AMR Action Fund has a goal to support two to four approvals of new antimicrobials by 2030, and one of its eight portfolio companies (https://lnkd.in/dAN3ppdX) gained an approval from the Food and Drug Administration in April 2024.
3) According to the Global AMR R&D Hub, which includes public and philanthropic funding, there are 195 active projects across the entire pipeline with a total value of US $559.5 million.
4) Financial problems of antibiotic small-medium enterprise (SME-biotech) companies: 1) Bankruptcy-Achaogen, Melinta Therapeutics; 2) Liquidation-Nabriva Therapeutics plc; 3) Distressed sale-Tetraphase Pharmaceuticals, Entasis Therapeutics, Paratek Pharmaceuticals; 4) Layoffs-Spero Therapeutics (4)
Momentum builds around new antibiotic business models
Highlights: 1) The Innovative Medicines Initiative's DRIVE-AB project joins the fray of task forces working to reinvigorate interest in antibiotics by developing reimbursement models that delink revenue from sales volume; 2) “We don’t want to just have another lament where everybody says ‘this is a problem, isn’t it a shame, wouldn’t it be great to solve it’,” says Judith Hackett, a project coordinator at DRIVE?AB and Global Payer Evidence Director at AstraZeneca; 3) A prize fund, for example, could buy out the relevant patents and then distribute the drugs. A report by Kevin Outterson for Chatham House notes that “the size of these prizes would have to be very significant, in the range of $500 million to more than $2 billion at first registration of an outstanding drug” (8)
A community-based approach to new antibiotic discovery
Highlights : 1) So, how many of the 80 million organic compounds in the CAS Registry might have the potential to be starting points for new antibacterial drugs? Applying a simple filter for antibacterial-like properties (calculated logP between –10 and 2, and molecular mass < 1,200 Da) to this group yielded 29 million compounds. The majority of these compounds are not commercially available, and most will never have been screened for antibacterial activity (6).
2) Compounds submitted to CO-ADD undergo a primary screen in a 384?well format against representatives of 5 key bacterial pathogens (Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA), as well as the fungi Cryptococcus neoformans and Candida albicans.
3) In the golden age of antibiotic discovery, most scientists would collaborate openly with each other. Now university technology transfer offices are reluctant to allow researchers to transfer compounds, assays or reagents without non?disclosure agreements and material transfer agreements (MTAs), which can take many months to agree — even for limited, short experiments. CO?ADD provides simple terms and conditions online and a signature-free MTA download if needed, which together warrant that the provider of the compound retains all rights to the compound, assay results and IP. See CO-ADD Community for Open Antimicrobial Drug Discovery
Bring the magic back to the bullets
The pharmaceutical industry, which 40 years ago was bringing to market approximately five new antibiotics every year, now only commercializes one or two at best. And a study carried out in 2004 reported only six antibacterials out of >500 drugs in late-stage clinical testing in big pharma firms. Part of the problem is simple economics. Most antibiotics generate only ~$200–300 million annually. They cure, rather than treat, patients in a few days and do not have to be prescribed for a lifetime, making them less attractive for investment. Patent lifetimes and clinical ‘misuse’ leading to resistance combine to restrict a drug’s commercial life to 8–10 years. And antibiotics for use against resistant bacteria are often reserved as drugs of last resort, further limiting sales (7).
Patents
Confronting antimicrobial resistance 2024 to 2029 and UK 20-year vision for antimicrobial resistance (4)
References
Thank you for this comprehensive update on the AMR research landscape. I have saved your article to share. We are one of the biotechnology companies researching AMR solutions. We received a grant from the NIH. At TAXIS Pharmaceuticals, Inc., we’re developing innovative solutions like TXA709, our investigational therapy designed to combat methicillin-resistant Staphylococcus aureus (MRSA).??? Learn more about TAXIS’ groundbreaking research in our blog: “Innovative Approaches to Antibiotic Resistance: The Promise of TXA709.” https://bit.ly/4focAmf
CEO at Securagen.ai | Adjunct Lecturer & Researcher at Hellenic Open University | Researcher at ReSEES, AUEB & Sustainable Development Unit, ATHENA RC | AI, Machine Learning & Data Science Specialist | (MCT)
2 个月Krzysztof Potempa, thank you for sharing such an insightful summary of antimicrobial resistance (AMR) and the challenges we face in addressing it. The emphasis on sustainable antibiotic discovery and the need for venture capital investment in antimicrobial research is particularly compelling. Combining traditional approaches with innovative solutions like machine learning could help bridge some of these gaps and accelerate breakthroughs. I recently explored the role of machine learning in combating AMR in my article: Machine Learning vs. Antimicrobial Resistance: A New Horizon in Healthcare. https://medium.com/@gferetzakis/machine-learning-vs-antimicrobial-resistance-a-new-horizon-in-healthcare-03620b79498f?source=friends_link&sk=873a7418f578ea904ae7082d8aa9b853