Antimicrobial resistance (AMR) is one of the most serious global health threats, contributing to an estimated five million deaths each year and placing increasing pressure on health systems worldwide. "AMR is undermining our ability to treat even routine infections, putting millions of lives at risk, especially in lower- and middle-income countries (LMICs)," said Trevor Mundel, President of Global Health at the Gates Foundation.
Researchers from Oxford's Centre for Medicines Discovery at the Nuffield Department of Medicine are among the founding members of a new international initiative, the Gram-Negative Antibiotic Discovery Innovator (Gr-ADI), launched today by the Novo Nordisk Foundation, Wellcome, and the Gates Foundation. The consortium aims to accelerate early-stage drug discovery for Gram-negative bacterial infections, with a focus on developing direct-acting, small-molecule antibiotics targeting Enterobacteriaceae.
The Oxford team is led by Dr Annette von Delft and includes collaborators Nicole Stoesser, Lizbe Koekemoer, Paul Brennan, Frank von Delft, Phil Fowler, Thomas Lanyon-Hogg, and Ed Griffen (MedChemica). The researchers will use Oxford's internationally recognised XChem crystallographic fragment screening platform to identify novel chemical starting points against three validated Klebsiella targets.
"Antimicrobial resistance, particularly in Gram-negative pathogens, presents one of the most urgent and technically challenging problems in modern medicine," said Dr Annette von Delft, Centre for Medicines Discovery, "Through Gr-ADI, we are combining structural biology, medicinal chemistry, and microbiology to build a robust, target-based discovery pipeline that has the potential to generate new antibiotics and be applied to future targets."
The team will generate new chemical matter designed to overcome key barriers in Gram-negative antibiotic discovery, including poor compound accumulation and rapid resistance development. Their approach prioritises compounds that accumulate in drug-resistant bacteria, targets conserved regions of bacterial proteins that are less prone to resistance, and optimises candidates for broad activity across Klebsiella species and related pathogens.
Ultimately, the researchers aim to establish a ready-to-use, target-based antimicrobial discovery pipeline that supports future antibiotic discovery efforts across a wider range of bacterial pathogens.
"The AMR crisis demands fresh thinking and a different way of working," concludes Marianne Holm, Vice President, Infectious Diseases at the Novo Nordisk Foundation. "The Gr‑ADI consortium aims to cut through barriers to progress, bringing together researchers aligned by a commitment to share knowledge openly and make new data, methods, and tools available to all. We hope their discoveries and data will benefit the whole field and bring us closer to urgently needed new antibiotics."