There is a disconnect between the content of the antimicrobial research and development (R&D) pipeline versus the magnitude of the antimicrobial resistance threat.  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. Therefore, new treatments that work in new ways, unaffected by current drug resistance mechanisms are required, Laura Piddock explains for the #FEMSmicroBlog ahead of World Antimicrobial Awareness Week (WAAW) on 18-24 November. #MicrobiologyEvents 

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 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.

90% of pre-clinical compounds are typically discarded/discontinued

—Dr. Patricia Bradford (personal communication to the author)

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 novel chemical entities (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.
3. Potentiators of aminoglycoside activity, and landscaping of efflux inhibitors.
4. Unrealised targets for antibacterial drug discovery; 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, GARDP 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), GARDP has four active hit expansion projects.

GARDP is 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. GARDP’s 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). GARDP also have six memory recovery and compound evaluation projects ongoing.

Through all this research GARDP 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.