Genome-wide assessment of the carriers involved in the cellular uptake of drugs: a model system in yeast
- Equal contributors
1 School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, UK
2 Manchester Interdisciplinary Biocentre, 131 Princess Street, Manchester, M1 7DN, UK
3 Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK
4 Cambridge Systems Biology Centre and Department of Biochemistry, University of Cambridge, Sanger Building, 80 Tennis Court Road, Cambridge, CB2 1GA, UK
BMC Biology 2011, 9:70 doi:10.1186/1741-7007-9-70Published: 24 October 2011
The 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.
To 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.
As 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.