How can we close the early discovery gap and improve our ability to discover new antibiotics?
– by Olga Genilloud

PLEASE NOTE: The Viewpoints on our website are to be read and freely shared by all. If they are republished, the following text should be used: “This Viewpoint was originally published on the REVIVE website revive.gardp.org, an activity of the Global Antibiotic Research & Development Partnership (GARDP).”

The views and opinions expressed in this article are solely those of the original author(s) and do not necessarily represent those of GARDP, their donors and partners, or other collaborators and contributors. GARDP is not responsible for the content of external sites.

The global antimicrobial resistance (AMR) crisis is one of the major global threats to human health, and the development of new treatments to tackle infectious diseases has been identified by the World Health Organization (WHO) as one of the most urgent needs. Nevertheless, despite the latest progress reported by the WHO (14 June 2024),¹ the current clinical development pipeline contains little innovation with many analogs of the same known antibiotics or not targeting critical pathogens. Furthermore, the preclinical pipeline is still too small to overcome the expected attrition in drug development. The early discovery gap is one of the major limitations to building the required innovative early preclinical pipeline and to responding to current and future needs in the development of new treatments. 

Current landscape of antibiotic early discovery 

For decades, early antibiotic discovery has been led by a strong pharmaceutical sector devoting large budgets, drug discovery expertise and technical resources to foster intensive early antibacterial programs. One by one, pharma companies have left the field due to the lack of success and return on investment. The adverse exploitation scenario determined a continued disinvestment, closure of R&D antibacterial research programs, and loss of key know-how as well as a highly specialized professional workforce. While many independent small and medium enterprises (SMEs) were established by former pharma experienced professionals from early programs licensed for large companies, most new SMEs are university spinouts with limited experience which are struggling to find investment sources to develop their preclinical programs. Existing push and pull incentives have been insufficient to support many SMEs to overcome the financial needs of the early development stages. Many SMEs did not succeed and eventually filed for bankruptcy during the clinical stages or even after commercialization.² In this adverse environment, very few companies with active preclinical development programs have continued to invest resources in early discovery.  

The complex and multidisciplinary nature of the antibiotic discovery process involves a broad range of areas of expertise that are nowadays dispersed and provided by a variety of individual stakeholders who are frequently poorly interconnected.

Today we can observe that early-stage antibiotic discovery is mainly conducted in academic settings. This large and global community primarily focuses on fundamental research; however, their lack of sufficient access to funding and the required expertise to progress antibiotics into development is limiting an efficient translation of this innovation into preclinical development.³ Another limitation is that many of the early-stage compounds lack the minimal in vitro and in vivo activity entry criteria for the early-stage accelerators. Initiatives such as CARB-X, ENABLE-2, INCATE, or the IMI AMR Accelerator are instrumental to ensure that early funds are not diluted. They are also important for ensuring the infrastructure and the preclinical and regulatory expertise required to advance new candidates into the development phases remain strong. Despite the positive impact of these initiatives and of different public-private partnerships such as GARDP in boosting the number of early-stage antibacterial programs, the number of programs supported globally are too low to fill the innovation gap. A much larger early discovery effort is needed to feed the preclinical programs and ensure that new classes of antibacterials targeting the critical resistant pathogens can finally enter into development.^4,5 

Challenges and actions needed

The complex and multidisciplinary nature of the antibiotic discovery process involves a broad range of areas of expertise that are nowadays dispersed and provided by a variety of individual stakeholders who are frequently poorly interconnected. This results in knowledge and funding gaps that limit the efficient progress of a program from the discovery to the development stages. The structural and organizational challenges in antimicrobial research need to be addressed urgently to curb lack of innovation observed in early discovery and enable all efforts to contribute to building the pipeline of new drugs that will be needed in a 10- to 15-year timeline. Three major challenges threaten the future outcomes of new antibiotic discovery. 

• Novel chemical scaffolds and new modes of action: this is one of the traditional and most relevant scientific challenges in antibacterial discovery that remains valid today. Despite intensive research and large investments done in the past, very few new chemical compound classes with a new mode of action and minimal cross-resistance with other antibiotics were developed. Most new approved antimicrobials are still improved versions of existing classes, and the preclinical pipeline is more frequently populated by alternative therapeutic strategies to respond to these limitations.^4,6 Many fundamental questions such as how to overcome entry barriers and natural efflux or how to mitigate emerging target-based resistance remain unsolved.^7,8 Despite the decrease of fundamental research and expertise in the field, new opportunities are also emerging from the application of ML-based modelling tools leveraging high-quality antimicrobial research data.⁹ These tools might contribute to revitalizing research and innovation in the field and open new avenues to identify and model new approaches to fight pathogens and explore the still underexploited chemical warfare provided by nature.¹⁰ Collaborations for cost-efficient experimental validation of these strategies based on novel targets and unexplored chemical spaces should leverage the expertise of existing highly specialized discovery platforms such as GARDP and a global network of experts.⁵ 

• Poor funding and lack of investment in antimicrobial research and development is observed at all stages. In the current landscape, SMEs struggle to raise private funding to support their programs whereas academics have seen decreased public funding in antimicrobial fundamental and applied research. Push and pull incentives in preclinical development have been instrumental in the progress of the existing pipeline but are insufficient to fill the development gap. Furthermore, the high-risk early discovery programs expected to fill the pipeline with innovative new antimicrobials are very difficult to fund in the academic environment.³ More specific funding calls supporting early discovery are clearly needed to engage academic and industry expertise to progress the number of new hypothesis-driven programs and have an impact on the early pipelines.  

• Talent and skills drain is another key limiting factor. The workforce engaged in antimicrobial research has been reduced dramatically in the last 20 years, both in the industrial and academic sectors. The decline in the number of researchers in the field and in their production of publications, and patents is significant compared to other fields.¹¹ Many researchers have retired or just left the field of antimicrobials due to the lack of investment and declining employment opportunities with the resulting drain in knowledge, expertise and talent. To overcome these challenges, increased and sustained global investment in the field needs critical support by policymakers not only to retain this talent and expertise but also to train the next generation of antimicrobial researchers. Ongoing efforts by some organizations leading the way to train early career professionals need to be reproduced at the global level to secure the workforce that will be needed to progress any new antimicrobial pipeline from early discovery to clinical development. 

Finally, large efforts are required from the public and private sectors to address these major challenges. This will only occur if the new national initiatives to repair the broken antibiotic market model are quickly implemented at the global level. Public-private partnerships, international initiatives, private stakeholders and policymakers have a role in paving the way towards the consolidation of the required global access infrastructures, expertise and high-quality science. Relevant public and private tailor-made investment funds are also needed to support the different stages of the discovery and development of new antimicrobials long-term. This will provide a new framework to leverage all the potential innovation in antimicrobial R&D arising from emerging SMEs and academic groups and to rebuild sustainable and innovative preclinical and clinical pipelines delivering the urgently needed future novel antimicrobials.  

References: 

1. World Health Organization. (2024). Antibacterial agents in clinical and preclinical development: an overview and analysis [Accessed 2024-06-17].  
2. Wells N, Nguyen VK, Harbarth S. (2024) Novel insights from financial analysis of the failure to commercialise plazomicin: Implications for the antibiotic investment ecosystem. Humanit Soc Sci Commun.
3. Miethke M, Pieroni M, Weber T, et al. 2021. Towards the sustainable discovery and development of new antibiotics. Nat Rev Chem.  
4. Theuretzbacher U, Baraldi E, Ciabuschi F, Callegari S. (2023). Challenges and shortcomings of antibacterial discovery projects. Clin Microbiol Infect.  
5. Piddock LJ V, Malpani R, Hennessy A. (2024) Challenges and Opportunities with Antibiotic Discovery and Exploratory Research. ACS Infectious Diseases.  
6.  Butler MS, Vollmer W, Goodall ECA, Capon RJ, Henderson IR, Blaskovich MAT. (2024) A Review of Antibacterial Candidates with New Modes of Action. ACS Infectious Diseases.   
7. Romano KP, Hung DT. (2023). Targeting LPS biosynthesis and transport in gram-negative bacteria in the era of multi-drug resistance. Biochim Biophys Acta Mol Cell Res.  
8. Fivenson EM, Dubois L, Bernhardt TG. (2024) Co-ordinated assembly of the multilayered cell envelope of gram-negative bacteria. Curr Opin Microbiol.   
9. Melo MCR, Maasch JRMA, de la Fuente-Nunez C. (2021) Accelerating antibiotic discovery through artificial intelligence. Commun Biol.
10. Walker AS, Clardy J. (2024). Primed for Discovery. Biochemistry. 
11. AMR Industry Alliance. (2024). Leaving the lab: Tracking the decline in AMR R&D professionals. [Accessed 2024-09-15]