Systematic exploration of synergistic drug pairs

Murat Cokol, Hon Nian Chua, Murat Tasan, Beste Mutlu, Zohar B. Weinstein, Yo Suzuki, Mehmet E. Nergiz, Michael Costanzo, Anastasia Baryshnikova, Guri Giaever, Corey Nislow, Chad L. Myers, Brenda J. Andrews, Charles Boone, Frederick P. Roth

Research output: Contribution to journalArticlepeer-review

182 Scopus citations

Abstract

Drug synergy allows a therapeutic effect to be achieved with lower doses of component drugs. Drug synergy can result when drugs target the products of genes that act in parallel pathways (' specific synergy'). Such cases of drug synergy should tend to correspond to synergistic genetic interaction between the corresponding target genes. Alternatively, ' promiscuous synergy' can arise when one drug non-specifically increases the effects of many other drugs, for example, by increased bioavailability. To assess the relative abundance of these drug synergy types, we examined 200 pairs of antifungal drugs in S. cerevisiae. We found 38 antifungal synergies, 37 of which were novel. While 14 cases of drug synergy corresponded to genetic interaction, 92% of the synergies we discovered involved only six frequently synergistic drugs. Although promiscuity of four drugs can be explained under the bioavailability model, the promiscuity of Tacrolimus and Pentamidine was completely unexpected. While many drug synergies correspond to genetic interactions, the majority of drug synergies appear to result from non-specific promiscuous synergy.

Original languageEnglish (US)
Article number544
JournalMolecular Systems Biology
Volume7
DOIs
StatePublished - 2011

Keywords

  • chemical genetics
  • drug combinations
  • drug discovery
  • genetic interactions

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