Novel immunomodulatory drugs for tuberculosis treatment
Can drugs that target host signaling pathways be used to eradicate antibiotic-resistant bacteria?
- 2014 - 2018
- Annemarie Meijer
- STW Open technology program
To overcome current limitations of antibiotic therapies, this project aims to use host‐targeted treatment as an innovative therapeutic approach.
Tuberculosis (TB) is a life-threatening disease that represents a major global health problem. Mycobacterium tuberculosis (Mtb) is becoming increasingly resistant to conventional antibiotic treatment, and there is currently no efficacious vaccine available that adequately prevents TB in adolescents and adults. Mycobacteria are highly potent in evading host immune responses and in fact often use host immune cells as a niche in which they can proliferate and survive. Pharmaceutical reprogramming of the immune system to kill intracellular mycobacteria would represent a therapeutic strategy that would be effective against currently untreatable strains and be less susceptible to developing drug resistance, since these compounds act on host and not on pathogen molecules.
The group of Prof. dr. Tom Ottenhoff and Dr. Mariëlle Haks at the LUMC has already identified novel lead chemical compounds for tuberculosis (TB) therapy, which act on specific host proteins that are manipulated by Mtb to promote its survival in host immune cells. In this project, we will test these lead compounds for activity against drug-resistant Mtb and apply them in combinatorial regimens together with classical antibiotics in vitro in infected human macrophage‐subsets and in vivo in zebrafish and mouse TB models. For the top emerging compounds, we will identify the host target proteins and pathways affected to support further development of drugs for clinical use. If proven efficacious, these new strategies may not only provide new solutions for TB treatment, but also be translatable to other chronic infectious disease caused by intracellular pathogens.
Kuijl C, Savage NDL, Marsman M, Tuin A, Janssen L, Egan DA, Ketema M, van de Nieuwendijk R, van den Eeden SJF, Geluk A, Poot A, van der Marel G, Beijersbergen RL, Overkleeft H, Ottenhoff THM, Neefjes JJ (2007) Intracellular bacterial growth is controlled by a kinase network around PKB/AKT1. Nature. 450:725-730
Meijer AH (2015) Protection and pathology in TB: learning from the zebrafish model. Semin Immunopathol, in press.