My laboratory has a major interest in bacterial protein toxins that cause human diseases. We study these remarkably toxic proteins both because they are high-value targets for therapeutic intervention by small molecules, and to exploit their unique cell-penetrating properties to design intracellular protein delivery vectors. Specifically, we are focused on three distinct aspects related to toxins: (1) on the molecular mechanism by which they cause disease; (2) on discovering and developing novel small-molecule therapeutics that block their action as a novel approach to treat certain toxin-driven infectious diseases; and, (3) on taking advantage of their unique cell-penetrating properties to engineer them into drug- delivery platforms.

Selected publications:

1. Zhang, Z., Park, M., Tam, J., Auger, A., Beilhartz, G.L., Lacy, D. B., Melnyk, R.A.. Translocation Domain Mutations Affecting Cellular Toxicity Identify the Clostridium difficile Toxin B Pore. Proc. Natl. Acad. Sci. USA (2014); 111(10): 3721-3726
2. Tam, J., Beilhartz, G.L., Auger, A., Gupta, P., Therien, A.G., Melnyk R.A.. Small Molecule Inhibitors of Clostridium difficile Toxin B-Induced Cellular Damage. Chemistry & Biology (2015); 22(2): 175-185.
3. Auger, A., Park, M, Nitschke, F., Minassian, L.M., Beilhartz, G.L., Minassian, B.A., Melnyk R.A.. Efficient Delivery of Structurally Diverse Protein Cargo into Mammalian Cells by a Bacterial Toxin. Molecular Pharmaceutics (2015); 3(12): 2962-2971
4. Chumbler, N.M., Rutherford, S.A., Zhang, Z., Farrow, M.A., Lisher, J.P., Farquhar, E., Giedroc, D.P., Spiller, B.W., Melnyk R.A., Lacy, D.B.. Crystal Structure of Clostridium difficile Toxin A. Nature Microbiology (2016); 1(1): 1-6.
5. Orrell KE, Tellgren-Roth, A., DiBernardo, M. Zhang, Z., Cuviello, F., Lundqvist, J., von Heijne, G., Nilsson, I.,, Melnyk RA.. Direct detection of membrane-inserting fragments defines the translocation pores of a family of pathogenic toxins. Journal of Molecular Biology (2018)