Optimization of Antibiotic Combinations using Organoids for treatment of Mycobacterium abscessus infections.

Therapeutics

Research Project: 2023-05-29 - 2026-05-28
Total sum awarded: €1 038 572

Mycobacterium abscessus (Mabs) is an emerging opportunistic pathogen responsible for lung infections particularly in cystic fibrosis patients. These infections are challenging worldwide due to their increasing incidence, their extreme resistance to available antimicrobial agents and the lack of new antibiotics in the pipeline. Antibiotic therapies are generally based on pharmacokinetic/pharmacodynamic (PK/PD) indices related to Minimal Inhibitory Concentration (MIC). Although useful for clinicians, MIC-based PK/PD is of little value with antibiotic combinations. In this context, pre-clinical in vitro investigations and semi-mechanistic PK/PD modelling for dosing regimen optimization of the antibiotic combinations appears to be the most promising approach. However, the accuracy of these PK/PD models is highly dependent of the quality of the in vitro data that generally raised a number of issues. Consequently, to improve the treatments of lung infections by Mabs, the objective of the ACOMa project is to implement a strong pre-clinical approach coupling a wide screening of new antibiotic combinations in vitro, the use of innovative lung organoids to consider the CF lung environment and semi-mechanistic PK/PD modelling to optimize antibiotic combinations. Finally, the most promising antibiotic combination-dosing regimen will be evaluated in vivo.

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  • Julien BUYCK, INSERM U1070, French National Institute of Health and Medical Research, France (Coordinator)
  • Peter SANDER, University of Zurich, Switzerland (Partner)
  • Céline COUGOULE, Institute of Pharmacology and Structural Biology, France (Partner)
  • Nicola Ivan LORE, San Raffaele Scientific Institute, Italy (Partner)
  • Lucas BOECK, University of Basel, Switzerland (Observer)

Mycobacterium abscessus (Mabs) is an emerging opportunistic pathogen responsible for lung infections particularly in cystic fibrosis patients. These infections are challenging worldwide due to their increasing incidence, their extreme resistance to available antimicrobial agents. The lack of new efficient antibiotics forces researchers and clinicians to optimize treatments with existing antibiotics, generally by combining several molecules together. In order to do so, using innovative approaches like organoids to study antibiotic efficacy are needed. Human lung organoid is a 3D cell clusters organized into organ-like constituting unprecedented innovative tools to evaluate antibiotic efficacy against Mabs by taking into account the CF lung environment allowing study and then limiting the use of animals. This approach coupled to mathematical simulations to optimize the concentration of antibiotic to use and to the understanding of Mabs resistance development during treatment will also bring new information to know whether to associate the different antibiotics together. The objective of the ACOMa project is to improve the treatment of patient by optimizing antibiotic combinations by implementing innovative approaches coupling the use of lung organoid with semi-mechanistic PK/PD models.

Call

2022 - Disrupting drug resistance using innovative design