High-throughput matrix screening identifies synergistic and antagonistic antimalarial drug combinations

Sci Rep. 2015 Sep 25;5:13891. doi: 10.1038/srep13891.

Abstract

Drug resistance in Plasmodium parasites is a constant threat. Novel therapeutics, especially new drug combinations, must be identified at a faster rate. In response to the urgent need for new antimalarial drug combinations we screened a large collection of approved and investigational drugs, tested 13,910 drug pairs, and identified many promising antimalarial drug combinations. The activity of known antimalarial drug regimens was confirmed and a myriad of new classes of positively interacting drug pairings were discovered. Network and clustering analyses reinforced established mechanistic relationships for known drug combinations and identified several novel mechanistic hypotheses. From eleven screens comprising >4,600 combinations per parasite strain (including duplicates) we further investigated interactions between approved antimalarials, calcium homeostasis modulators, and inhibitors of phosphatidylinositide 3-kinases (PI3K) and the mammalian target of rapamycin (mTOR). These studies highlight important targets and pathways and provide promising leads for clinically actionable antimalarial therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Antimalarials / pharmacology*
  • Autophagy / drug effects
  • Calcium / metabolism
  • Cluster Analysis
  • Disease Models, Animal
  • Drug Antagonism
  • Drug Synergism
  • Drug Therapy, Combination
  • High-Throughput Screening Assays*
  • Homeostasis / drug effects
  • Humans
  • Inhibitory Concentration 50
  • Malaria / drug therapy
  • Malaria / parasitology
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Oxidative Stress / drug effects
  • Parasitic Sensitivity Tests*
  • Phagosomes / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Plasmodium / drug effects*
  • Plasmodium / metabolism

Substances

  • Antimalarials
  • Phosphoinositide-3 Kinase Inhibitors
  • Calcium