This post was written by Laura Piddock, Scientific Director at Global Antibiotic Research & Development Partnership (GARDP), and is jointly shared on the FEBS Network and the #FEMSmicroBlog, the blog from the Federation of European Microbiological Societies.

There is a disconnect between the content of the antimicrobial research and development (R&D) pipeline versus the magnitude of the antimicrobial resistance threat. Most new agents in clinical development are of existing classes, such as an old beta-lactam combined with a new beta-lactamase inhibitor with activity against common Enterobacterales with specific resistances, such as extended-spectrum beta-lactamases. There has been a limited focus or attempt to develop new treatments for those pathogens deemed by the World Health Organization (WHO) as a critical priority for new treatments. This includes carbapenem-resistant bacteria and typically, these are Gram-negative bacterial species. There remains an innovation challenge due to the need to find a compound that will either act on the outer membrane or enter the bacterial cell and stay inside, i.e., not succumb to bacterial efflux. Therefore, new treatments that work in new ways, unaffected by current drug resistance mechanisms are required.

Discovering and carrying out pre-clinical development of potential new treatments is a process that covers various stages, including basic science, target identification, target assessment and validation, hit finding, such as via phenotypic high-throughput screening, hit expansion, hit to lead, and lead optimisation. Then it requires all of the necessary activities to prepare a data package showing that a candidate is ready for an Investigational New Drug (IND) Application, and proceed into clinical development by first testing for safety in humans.

The attrition rates for drug discovery are extremely high for innovative approaches and have been cited as low as 0.6% of compounds when including novel chemical entities (NCEs) discovered in academia (Farrell et al., 2018). Dr Patricia Bradford, who has worked at some of the largest pharmaceutical companies in the world, including AstraZeneca, Novartis, and Wyeth, has estimated that 90% of pre-clinical compounds are typically discarded/discontinued (personal communication). Due to this high attrition rate of potential products entering clinical development, it was estimated by the WHO in 2019 that around 10,000 NCEs need to be discovered to give rise to more than 100 projects/candidates in the pre-clinical phase and to ensure that sufficient numbers enter clinical development such that a few eventually reach patients.

The Global Antibiotic Research & Development Partnership (GARDP) is a not-for-profit research and development (R&D) foundation based in Geneva, Switzerland that operates in partnership with organisations globally. It was originally created by the WHO and incubated until 2019 by the Drugs for Neglected Diseases initiative (DNDi) to address global public health needs by developing and delivering new or improved antibiotic treatments while facilitating sustainable access.

GARDP focuses much of its activities and expenditure on clinical development in partnership with others. However, it also has a Discovery and Exploratory Research programme aimed at addressing critical gaps in the global pre-clinical antibiotic pipeline. Research focuses on Gram-negative bacteria and seeks NCEs with the potential to become new drugs active against Klebsiella pneumoniae and/or Acinetobacter baumanii and with attributes in line with the needs of GARDP’s clinical development portfolio.

Current early discovery activities are divided into five research areas: (1) Small molecules, including identification of unexploited libraries and in silico analyses to identify chemical matter with the properties typically associated with good antibacterial activity against Gram-negative bacteria, and phenotypic screening of libraries that have not been screened by others. (2) Natural products, focusing on untapped microbes, and new technologies to identify metabolites with antibacterial activity anti-bacterial activity. (3) Potentiators of aminoglycoside activity, and landscaping of efflux inhibitors. (4) Unrealised targets for antibacterial drug discovery (Theuretzbacher et al., 2023); current work is focusing on target assessment and validation on ~10 targets. (5) Undeveloped agents that includes due diligence of old compounds (memory recovery project) and evaluation of compounds discovered by others with potential for new medicinal chemistry starting points.

So far across these five themes, we have completed 26 projects and have 22 in progress. This includes in silico analysis of over 3.5 million compounds leading to a bespoke library for phenotypic screening. Based on hits from our high-throughput phenotypic screening of more than 136,000 compounds for activity against multidrug-resistant, Gram-negative bacteria (including NCEs from libraries generously shared with us by Japanese pharmaceutical companies), we have four active hit expansion projects. We are currently following up on one series of potentiators and carrying out a medicinal chemistry review of efflux inhibitors based on information obtained for our landscaping project. Our work on validation and assessment of unrealised targets in Gram-negative bacteria has used a variety of computational tools and includes a collaboration with Google DeepMind (Alphafold). We also have six memory recovery and compound evaluation projects ongoing.

Through all this research we have built a network of global partners on this work in over eight countries and will continue to develop new collaborations as we develop our projects. In the coming years, our mission is to advance these projects through the discovery research stages to eventually produce pre-clinical candidates with the desired profile to meet the ever-growing global antimicrobial resistance threat.

Written by Laura Piddock, Scientific Director, the Global Antibiotic Research & Development Partnership

Laura Piddock joined the Global Antibiotic Research and Development Partnership (GARDP) in January 2018. As GARDP’s Scientific Director, Laura leads the Discovery and Exploratory Research programme, as well as the Scientific Affairs & REVIVE programme. She also contributes to GARDP’s Policy & Advocacy activities.

Laura has been at the forefront of antimicrobial research for over 30 years, beginning her career in a hospital and successfully integrating this background with academic research. Laura is Emeritus Professor of Microbiology at the University of Birmingham, UK, where she led a team researching the mechanisms of action and resistance to antibiotics and biocides, and in the last decade her academic research included drug discovery. She has collaborated with Pharma on many projects on new antibiotics. She has published widely in international peer reviewed journals (>200 original articles, >20 non-research policy original articles, 50 invited review articles, 21 research letters, 157 conference proceedings, 6 chapters in academic books). Laura has contributed to nine reports and advised organisations such as the World Health Organization, and scientific data from her team has been used by national governmental agencies. She has given over 200 lectures at international conferences. She has an H-index of 96.

Laura is an enthusiastic communicator about antibiotic resistance and the lack of new antibiotics. She has been interviewed by local, national and international media (print, radio, television and digital), and advised on and appeared in several documentaries for numerous global networks including BBC (One, Two, Four, Radio 2, Radio 4, Radio 5 Live), Al Jazeera, CNN, Channel 4 and Sky News.

In 2001, Prof. Piddock was made a Fellow of the American Academy of Microbiology. In 2006, Laura became the first woman President of the British Society for Antimicrobial Chemotherapy (BSAC). In 2017, she was appointed as a founding Fellow of the European Society of Clinical Microbiology and Infectious Diseases. From 2012-2017, Laura was the BSAC Chair in Public Engagement. Laura was the Chair of the EU Joint Programming Initiative on Antimicrobial Resistance (JPI-AMR) Scientific Advisory Committee 2017-2018. In 2019, Laura was awarded the Garrod Medal for her work on AMR.

References:

• WHO list of bacteria for which new antibiotics are urgently needed (Priority Pathogen List). 27 February 2017.
• Farrell LJ, Lo R, Wanford JJ, Jenkins A, Maxwell A, Piddock LJV. Revitalizing the drug pipeline: AntibioticDB, an open access database to aid antibacterial research and development. J Antimicrob Chemother. 2018 Sep 1;73(9):2284-2297. doi: 10.1093/jac/dky208. PMID: 29897476.
• Theuretzbacher U, Blasco B, Duffey M, Piddock LJV. Unrealized targets in the discovery of antibiotics for Gram-negative bacterial infections. Nat Rev Drug Discov. 2023 Oct 13. doi: 10.1038/s41573-023-00791-6. Epub ahead of print. PMID: 37833553.

Top image courtesy of the Institut Pasteur Korea