Systematic exploration of synergistic drug pairs

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. Two types of drug synergy, genetic and promiscuous, are explored in S. cerevisiae . The results suggest that promiscuous synergy predominates, and that propensity to synergize is an intrinsic drug property with the potential to accelerate the search for synergistic drug combinations. Synopsis Two types of drug synergy, genetic and promiscuous, are explored in S. cerevisiae . The results suggest that promiscuous synergy predominates, and that propensity to synergize is an intrinsic drug property with the potential to accelerate the search for synergistic drug combinations. Discovered 37 synergistic interactions among antifungal chemicals Promiscuous synergy is the predominant form of drug synergy Rate of synergy is an intrinsic property of drugs that can guide searches for drug synergy