title: High-throughput matrix screening identifies synergistic and antagonistic antimalarial drug combinations.
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.
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD.
authors.forename: Bryan T
authors.initials: BT
authors.lastname: Mott
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Eastman
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD.
authors.forename: Rajarshi
authors.initials: R
authors.lastname: Guha
authors.affiliation: Department of Chemistry, Georgetown University, 37th and O St., NW, Washington, DC.
authors.forename: Katy S
authors.initials: KS
authors.lastname: Sherlach
authors.affiliation: Department of Chemistry, Georgetown University, 37th and O St., NW, Washington, DC.
authors.forename: Amila
authors.initials: A
authors.lastname: Siriwardana
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD.
authors.forename: Paul
authors.initials: P
authors.lastname: Shinn
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD.
authors.forename: Crystal
authors.initials: C
authors.lastname: McKnight
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD.
authors.forename: Sam
authors.initials: S
authors.lastname: Michael
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
authors.forename: Norinne
authors.initials: N
authors.lastname: Lacerda-Queiroz
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD.
authors.forename: Paresma R
authors.initials: PR
authors.lastname: Patel
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
authors.forename: Pwint
authors.initials: P
authors.lastname: Khine
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD.
authors.forename: Hongmao
authors.initials: H
authors.lastname: Sun
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD.
authors.forename: Monica
authors.initials: M
authors.lastname: Kasbekar
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD.|Department of Chemistry, Georgetown University, 37th and O St., NW, Washington, DC.
authors.forename: Nima
authors.initials: N
authors.lastname: Aghdam
authors.affiliation: Department of Pharmaceutical Chemistry, Small Molecule Discovery Center, University of California, San Francisco, CA.
authors.forename: Shaun D
authors.initials: SD
authors.lastname: Fontaine
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD.
authors.forename: Dongbo
authors.initials: D
authors.lastname: Liu
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD.
authors.forename: Tim
authors.initials: T
authors.lastname: Mierzwa
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD.
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Mathews-Griner
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD.
authors.forename: Marc
authors.initials: M
authors.lastname: Ferrer
authors.affiliation: Department of Pharmaceutical Chemistry, Small Molecule Discovery Center, University of California, San Francisco, CA.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Renslo
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD.|National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.
authors.forename: James
authors.initials: J
authors.lastname: Inglese
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
authors.forename: Jing
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Department of Chemistry, Georgetown University, 37th and O St., NW, Washington, DC.|Department of Biochemistry, Cellular and Molecular Biology and Center for Infectious Diseases, Georgetown University, 37th and O St., NW, Washington, DC.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Roepe
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
authors.forename: Xin-Zhuan
authors.initials: XZ
authors.lastname: Su
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Thomas
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D016000:Cluster Analysis; D004195:Disease Models, Animal; D004336:Drug Antagonism; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D057166:High-Throughput Screening Assays; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D021261:Parasitic Sensitivity Tests; D010588:Phagosomes / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010961:Plasmodium / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000962:Antimalarials; D000081082:Phosphoinositide-3 Kinase Inhibitors; D002118:Calcium