title: Systematic exploration of synergistic drug pairs.
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.
authors: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. cokol@sabanciuniv.edu
authors: Murat
authors: M
authors: Cokol
authors: Hon Nian
authors: HN
authors: Chua
authors: Murat
authors: M
authors: Tasan
authors: Beste
authors: B
authors: Mutlu
authors: Zohar B
authors: ZB
authors: Weinstein
authors: Yo
authors: Y
authors: Suzuki
authors: Mehmet E
authors: ME
authors: Nergiz
authors: Michael
authors: M
authors: Costanzo
authors: Anastasia
authors: A
authors: Baryshnikova
authors: Guri
authors: G
authors: Giaever
authors: Corey
authors: C
authors: Nislow
authors: Chad L
authors: CL
authors: Myers
authors: Brenda J
authors: BJ
authors: Andrews
authors: Charles
authors: C
authors: Boone
authors: Frederick P
authors: FP
authors: Roth
mesh_terms: D000935:Antifungal Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D004347:Drug Interactions; D004357:Drug Synergism; D010419:Pentamidine / Q000493:pharmacokinetics / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D016559:Tacrolimus / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D010419:Pentamidine; D016559:Tacrolimus