A functional variomics tool for discovering drug-resistance genes and drug targets

Cell Rep. 2013 Feb 21;3(2):577-85. doi: 10.1016/j.celrep.2013.01.019. Epub 2013 Feb 14.

Abstract

Comprehensive discovery of genetic mechanisms of drug resistance and identification of in vivo drug targets represent significant challenges. Here we present a functional variomics technology in the model organism Saccharomyces cerevisiae. This tool analyzes numerous genetic variants and effectively tackles both problems simultaneously. Using this tool, we discovered almost all genes that, due to mutations or modest overexpression, confer resistance to rapamycin, cycloheximide, and amphotericin B. Most significant among the resistance genes were drug targets, including multiple targets of a given drug. With amphotericin B, we discovered the highly conserved membrane protein Pmp3 as a potent resistance factor and a possible target. Widespread application of this tool should allow rapid identification of conserved resistance mechanisms and targets of many more compounds. New genes and alleles that confer resistance to other stresses can also be discovered. Similar tools in other systems, such as human cell lines, will also be useful.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Amphotericin B / pharmacology
  • Antifungal Agents / pharmacology*
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cycloheximide / pharmacology
  • Drug Resistance, Microbial / genetics*
  • Mutation
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Proteolipids / antagonists & inhibitors
  • Proteolipids / genetics
  • Proteolipids / metabolism
  • Ribosomal Proteins / antagonists & inhibitors
  • Ribosomal Proteins / genetics
  • Ribosomal Proteins / metabolism
  • Saccharomyces cerevisiae / drug effects*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae Proteins / antagonists & inhibitors
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism
  • Sirolimus / pharmacology

Substances

  • Antifungal Agents
  • Cell Cycle Proteins
  • PMP3 protein, S cerevisiae
  • Phosphoinositide-3 Kinase Inhibitors
  • Proteolipids
  • RPL28 protein, S cerevisiae
  • Ribosomal Proteins
  • Saccharomyces cerevisiae Proteins
  • Amphotericin B
  • Cycloheximide
  • TOR2 protein, S cerevisiae
  • Sirolimus