Clionamines Stimulate Autophagy, Inhibit Mycobacterium tuberculosis Survival in Macrophages, and Target Pik1
This week we profile a recent publication in Cell Chemical Biology from the lab of Dr. Raymond Andersen
(pictured, top right) in collaboration with Drs. Yossef Av-Gay (center) and Michele Roberge (left) at UBC.
The first authors are Drs. Rosanne Persaud, Sheena Li, and Joseph Chao (bottom right).
Can you provide a brief overview of your lab’s current research focus?
The research in my lab is all focused on exploring the potential of marine natural products to act as lead compounds for the development of new drugs to treat human diseases or as research tools to identify new drug targets.
What is the significance of the findings in this publication?
This publication has identified a new drug target for the development of ‘host directed therapies’ to treat tuberculosis, the main cause of deaths worldwide resulting from a bacterial infection.
What are the next steps for this research?
This project started with collaborations with Michel Roberge and Yossi Av-Gay. Michel was interested in activators of autophagy and Yossi was interested in the potential of autophagy activators as treatments for tuberculosis. Michel screened our marine natural product extract library for activation of autophagy and he identified the crude extract of a sponge collected in South Africa as being a potent hit. In collaboration with Michel, we isolated the pure natural product clionamines that were responsible for the autophagy activation of the crude extract and elucidated their novel chemical structures. We also developed a laboratory synthesis of the clionamines that gave us access to unnatural analogs. Yossi then tested the natural products and the synthetic analogs for their ability of inhibit the growth of Mtb in macrophage cells. Once Yossi had demonstrated that the clionamines effectively inhibited the growth of Mtb in macrophages, the consortium of co-authors set out to identify the protein molecular target of the clionamines. The results of that work is what is described in the manuscript.
The work has identified a potential new drug target and also a general chemical class of compounds that hit the target and inhibit the growth of Mtb in macrophages. We have shown that a drug fluoxetine currently in clinical use for another purpose hits the same target as the clionamines and it also inhibits the growth of Mtb in macrophages. The hope would be that this drug or other approved drugs or new drugs that hit this target could be repurposed or developed from scratch for the treatment of tuberculosis as a result of our research.
Last week we were contacted by a Biotech startup in Sweden that has a potent and selective PI4KB analog in phase I clinical trials for another disease. Yossi has agreed to test their inhibitor in his Mtb assays. We are excited by the possibility of this PI4KB inhibitor being also tested as a novel treatment for tuberculosis. This is exactly the outcome we hoped for when our work was published.
If you’d like to mention your funding sources, please list them.
CIHR and NSERC funded most of this research.