Discovery & Exploratory
Growing drug resistance is outpacing the development of antibiotics for the most difficult-to-treat infections. What is needed are not just new or more antibiotics, but rather innovative antibiotics that target resistant and deadly pathogens. Producing such antibiotics starts with the earliest stage of drug development: discovery and exploratory research. GARDP is harnessing 21st-century technologies and engaging in strategic partnerships to advance the discovery of compounds that have the potential to become the innovative antibiotics of the future.
Use novel technologies and the best science to find new substances (compounds) with potential for drug development
Identify novel compounds that can be developed into new antibiotic treatments for drug-resistant priority pathogens, Klebsiella pneumoniae and Acinetobacter baumannii
“The discovery of new antibiotic compounds has changed massively over the past few decades. Science has become much more collaborative and has seen the introduction of advanced, new technologies and computational power. There is great potential to discover compounds that could become the life-saving antibiotics of the future.”
– Laura Piddock, Scientific Director, GARDP
The drug development funnel
High-throughput screening and profiling compounds with activity against drug-resistant Klebsiella pneumoniae and Acinetobacter baumannii
GARDP has screened thousands of compounds (i.e., substances synthesised in laboratory) and natural products (that are produced by microbes) for antibiotic activity. The goal is to identify compounds with the potential either to become a new antibiotic, or to restore activity of an existing antibiotic that has been affected by drug resistance.
- GARDP created a screening strategy, implemented by Institut Pasteur Korea (IPK), for its work.
- GARDP established an AMR Screening Consortium to screen compounds that had never been tested for antibiotic activity. As part of the consortium agreement, three Japanese pharmaceutical companies—Eisai, Takeda and Daiichi Sankyo—gave GARDP access to their libraries of proprietary chemical compounds. GARDP plans to screen libraries from two more companies soon.
- GARDP screened the ReFRAME compound library from the non-profit research institute Calibr (part of Scripps Research, USA) for substances with the potential to restore activity to antibiotics increasingly affected by drug resistance. Current work is testing the activity of the promising compounds (“hits”) and synthesising new compounds (“analogues”) based on the structure of the hits identified by high-throughput screening.
- GARDP partnered with Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) to screen a library of natural product extracts for antibiotic activity and to identify and characterise any active compounds.
- GARDP has partnered with Sumitomo Pharma to screen a set of compounds from its compound library.
- GARDP has partnered with Mitsubishi Tanabe Pharma Corporation to access over 50,000 compounds from MTPC’s compound library.
As a next step in antibiotic discovery work, GARDP is now testing and optimizing promising compounds (“hits”). This work will make it possible to determine the viability of compounds for development into pre-clinical candidates (the basis for a new drug).
- GARDP has signed a Master Service Agreement with TCG Life Sciences (TCGLS) in India to synthesise new analogues. Testing at TCGLS will also help identify those compounds that are non-toxic and drug-like (i.e. the chemical structures of the compounds have the features required by drugs).
Horizon scanning reports and other exploratory activities for antibiotic research and development
GARDP carries out studies and activities to further antibiotic discovery, research and development. In “Horizon scanning for antibacterial drug discovery projects focused on WHO critical priority Gram-negative bacterial pathogens” (2021), GARDP found that although the early discovery antibacterial pipeline is scientifically diverse, it is insufficient to deliver the necessary antibiotic treatments for infections caused by Gram-negative bacteria in the future. GARDP also has a project to identify unexploited bacterial targets with potential for antibiotic drug discovery programmes that focus on Gram-negative bacteria (especially Klebsiella pneumoniae and Acinetobacter baumannii) and direct-acting small molecules. In addition, GARDP has reviewed pre-clinical studies of efflux inhibitors (that facilitate drug penetration into bacteria). The combination of these new chemical entities with antibiotics have great potential to overcome antibiotic resistance.
Revamping an antibiotic database for 21st-century research
GARDP, in partnership with the University of Leeds and the University of Edinburgh, is updating AntibioticDB. This searchable online database contains key information about antibiotics at all stages of development and post-approval, such as the target pathogens (spectrum of activity) and the highest development stage, as well as links to original articles and the IUPHAR/BPS Guide to Pharmacology. The database contributes to antibiotic development by making it easy to locate antibiotics at all stages of development, as well as those approved for use in people. The database also includes undeveloped compounds, and in some cases, the reason for lack of development (e.g., toxicity, funding gaps or changes in business strategy).
- SCREENED just under 100,000 compounds plus extracts of natural compounds for antibiotic activity
- EVALUATED 10 chemical series (each corresponding to a “hit” compound) for antibiotic activity
- CURRENTLY TESTING chemical series (each corresponding to a “hit” compound) for potential for further drug development
About discovery and exploratory research
About discovery and exploratory research
In 1928, Alexander Fleming discovered antibiotics by chance when a mould got into an uncovered plate of Staphylococcus bacteria. That discovery revolutionized modern medicine and led to the “golden age” of antibiotic discovery in the 1950s and 60s.
But almost immediately after scientists discovered antibiotics, they realized that bacteria could become drug-resistant.
The number of drug-resistant infections continues to rise inexorably while investment in new antibiotics has fallen (due to, for example, inadequate financial incentives and greater difficulty discovering and designing new compounds in the decades following the “golden age” of antibiotic discovery).
Moreover, the introduction of genuinely innovative antibiotics with new chemical structures (“classes”) has stagnated—no new class of antibiotics has been developed since the 1980s. Since resistance to one antibiotic often translates into resistance to its entire class, new antibiotic classes are essential to counter drug resistance.
Unfortunately, resistance is growing faster than new antibiotics are being developed. In 2021, the World Health Organization reported the world is still failing to develop the antibiotic treatments that are desperately needed for the most dangerous bacteria. Discovery and exploratory research for new compounds must target these bacteria to contribute to the development of the innovative antibiotics of the future.