AMR: Partnership set to improve in vivo antibiotics testing

The development of novel antibiotics is crucial in the fight against antimicrobial resistance (AMR) but has been neglected for decades due to a lack of development incentives. Another difficulty is the assessment of the efficacy of novel antibiotics targeting multidrug-resistant Gram-negative pathogens in vivo using infection models. Usually, preclinical in vivo PK/PD models play a crucial role in antimicrobial efficacy investigations and provide the basis for the selection of dosing regimens in clinical applications. However, there are a lot of models in use that do not allow comparison of results. The COMBINE consortium is validating a mouse pneumonia model that could serve as a globally harmonised standard pre-clinical model for the AMR community. Using a small panel of reference and clinical Pseudomonas aeruginosa and Klebsiella pneumoniae isolates, the IMI-funded consortium has so far identified a set of strains with suitable virulence that met the endpoint criteria set up.

Five partners have now joined forces to evaluate this pneumonia model: The Innovative Medicines Initiative project COMBINE provides its in vivo pneumonia model to test small molecule antibiotics that fight Gram-negative bugs from the CDC and WHO priority pathogen list. This model is now being evaluated through a unique collaboration with funding, drug development, mathematic modelling, CRO, and lab experts from the AMR community: CARB-X, CAIRD, iiCON and Eurofins division Pharmacology Discovery Services. Data from the model will support the establishment of a reference strain bank of clinically relevant, well-characterised Gram-negative strains. COMBINE is also providing a framework to bridge the gap between preclinical data and clinical outcomes using mathematical modelling approaches.

According to the partnership agreement, COMBINE, CARB-X, CAIRD, iiCON and Eurofin’s Pharmacology Discovery Services will share data and expertise, and exchange ideas on study design for validation and benchmarking studies. The work on the pneumonia model is led by a team at Statens Serum Institut in Denmark, with COMBINE in vivo experiments will be performed at three different project partner sites: the Statens Serum Institut, the Paul-Ehrlich-Institut and at GlaxoSmithKline (GSK) in order to test inter-laboratory reproducibility.   

 “I am pleased that the protocol that COMBINE has developed for the standard pneumonia model works well with the isolates and antibiotics tested so far,” said Prof. Dr. Lena Friberg from Uppsala University, who heads the COMBINE efforts on translation. Further studies are now in progress to fully characterise the model, and we look forward to making the protocol available to the AMR community,“ she added.

Boston-headquartered AMR MDR antibiotics early development funding organisation CARB-X will play an important role in this work by supporting the validation of the pneumonia model with approved antibiotics used in clinical settings, with CAIRD leading the work to provide a benchmark for new experimental antibiotics through back-translation of clinical data from human plasma and lungs. iiCON is another strategic partner, working with the Antimicrobial Pharmacodynamics and Therapeutics (APT) group at the University of Liverpool and Infex Therapeutics to support the development of experimental models of invasive bacterial and fungal diseases and mathematical modelling to ensure optimal dose selection. Another important part of the work will be facilitated by Eurofins’ Pharmacology Discovery Services, supplying data on the efficacy of standard antibiotics in mouse lung infection models.

COMBINE has a coordinating role in the AMR Accelerator, a cluster of public-private partnership projects funded by the Innovative Medicines Initiative (IMI). The initiative brings together academia, pharma industry, patient organisations, non-profits and SMEs to develop a robust pipeline of antibiotics. “We are excited to bring standardised tools to those working to fill the pipeline with new antibiotics, and proud to be part of a community of stakeholders working together to combat antimicrobial resistance”, said Anders Karlén, Professor of Computer-Aided Drug Design at University Uppsala and academic project coordinator of COMBINE.  

Scientists interested in joining COMBINE efforts (by sharing preclinical or clinical pneumonia data, conducting validation studies in their labs or sharing bacterial isolates) are welcome to contact the coordinator at IMI-COMBINE@pei.de.