Abstract
BackgroundThe uptake of drugs into cells has traditionally been considered to be predominantly via passive diffusion through the bilayer portion of the cell membrane. The recent recognition that drug uptake is mostly carrier-mediated raises the question of which drugs use which carriers.ResultsTo answer this, we have constructed a chemical genomics platform built upon the yeast gene deletion collection, using competition experiments in batch fermenters and robotic automation of cytotoxicity screens, including protection by 'natural' substrates. Using these, we tested 26 different drugs and identified the carriers required for 18 of the drugs to gain entry into yeast cells.ConclusionsAs well as providing a useful platform technology, these results further substantiate the notion that the cellular uptake of pharmaceutical drugs normally occurs via carrier-mediated transport and indicates that establishing the identity and tissue distribution of such carriers should be a major consideration in the design of safe and effective drugs.
Highlights
The uptake of drugs into cells has traditionally been considered to be predominantly via passive diffusion through the bilayer portion of the cell membrane
A particular benefit of S. cerevisiae is the availability of a barcoded series of deletion mutants [16], whose relative rates of growth/survival can be tested in competition experiments
Canavanine is an arginine analogue that is readily incorporated into proteins, producing a toxic effect
Summary
The uptake of drugs into cells has traditionally been considered to be predominantly via passive diffusion through the bilayer portion of the cell membrane. We recognized that if a drug is toxic when present at a high concentration inside the cell, but requires the activity of a carrier to be taken up by the cell, a strain with no or reduced carrier activity should be relatively resistant to the drug and survive better in competition experiments when compared to strains with normal uptake activity. This analysis predicts that if another non-toxic (and possibly ‘natural’ [21]) substrate for the carrier is known, this will compete with the toxic drug for uptake into the wild-type (WT) strain (assuming equivalent binding sites), thereby conferring phenotypic protection against toxicity
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