Varied mechanisms for the neutralization of biological toxins using natural products.

Abstract

Natural proteinaceous toxins in the pore-forming class and misfolded protein oligomers can interact with and perturb cell membranes, culminating in the death of the cell. Finding antidotes for such biologically toxic species is important towards the development of medical countermeasures for potential biological threat agents and treatments for neurodegenerative diseases. Using small molecule natural products, we have identified diverse mechanisms that result in the neutralization of model pore-forming toxins, including melittin from honeybee venom and alpha-hemolysin from Staphylococcus aureus. Through a combination of biophysical studies to interrogate the physico-chemical properties of the toxins in the presence of natural products and tissue culture experiments, we show that specific aminosterols and tea catechins act as therapeutics for these toxins. In particular, aminosterols attenuated toxin activity by targeting the cell membrane rather than the toxin directly, while catechins modulated the size-hydrophobicity-toxicity relationship of the proteins. These findings draw parallels to the mechanisms by which certain small molecules, including aminosterols, can suppress the toxicity caused by endogenous aggregates of misfolded proteins in a range of neurodegenerative diseases, in particular Alzheimer's and Parkinson's diseases, and they highlight modes by which biological toxins can be neutralized by natural products.