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closeKudos on the excellent use of the yeast model
Posted by madamescientist on 22 May 2012 at 20:30 GMT
Nice work, Ethan! There are at least two reasons I like this study. First, of course, is the use of yeast to model lysosomotropic effects of sertraline that contribute to toxicity in patients. Have you tried to reproduce your findings in a cell culture model (using bafilomycin, for instance)? We see a lot of overlap with our studies using amiodarone, another cationic amphipathic FDA approved drug that has toxic side effects.
Second, I like the idea of exploiting FDA approved drugs like amiodarone and sertraline as novel antifungals, against pathogenic yeasts and other microorganisms. We've seen limited efficacy against C. albicans, particularly against drug resistant strains and as chemosensitizers in combination with more conventional antifungals. Given that they target the membrane rather than a specific protein or pathway, drug resistance against CAD s does not appear so readily.
RE: Kudos on the excellent use of the yeast model
eperlste replied to madamescientist on 23 May 2012 at 04:06 GMT
Thanks!
In response to your first point the answer is yes. We are currently working with the rat neuronal cell line PC12. Our goal for the next paper is to replace yeast cells with PC12 in all the assays described in this PLoS ONE paper. For starters, we've been using tritiated sertraline in cellular uptake assays with PC12 cells. We already have data showing that [3H]sertraline uptake is bafilomycin-sensitive. So the lysosomotropic component of sertraline uptake is definitely conserved, and we're now investigating the clathrin component.
I should caution that I suspect that membrane accumulation may be relevant to the therapeutic effects of sertraline, not just the unwanted side effects. Recall that SSRIs are actually quite tolerable in most patients, at least compared to older tricyclic antidepressants which were largely replaced by SSRIs starting in the 90s. So outright toxicity of SSRIs in humans is supposedly rare.
As to your second point I agree that repositioning/repurposing SSRIs as antifungal agents is an attractive idea that was first proposed by the Austrian group which originally published on the antifungal effect of sertraline on Candida cells. I think you're correct in stating that the paths to clinical drug resistance stemming from a membrane-based cytotoxicity would be fewer for pathogenic yeast, especially if a cationic amphipath were given in combination with other classes of antifungals. But again I would caution that just because the membrane is a drug target doesn't mean that the drug-membrane interaction is non-specific. Phospholipids are chiral after all, and there is a tremendous structural diversity of lipid molecules in cellular membranes, from head group diversity to backbone diversity to acyl chain diversity. Our notions of specificity are shaped (no pun intended) by drug-protein interactions. Drug-membrane interactions are still terra incognita, IMHO.