title: A semi-automated luminescence based standard membrane feeding assay identifies novel small molecules that inhibit transmission of malaria parasites by mosquitoes.
abstract: Current first-line treatments for uncomplicated falciparum malaria rapidly clear the asexual stages of the parasite, but do not fully prevent parasite transmission by mosquitoes. The standard membrane feeding assay (SMFA) is the biological gold standard assessment of transmission reducing activity (TRA), but its throughput is limited by the need to determine mosquito infection status by dissection and microscopy. Here we present a novel dissection-free luminescence based SMFA format using a transgenic Plasmodium falciparum reporter parasite without resistance to known antimalarials and therefore unrestricted in its utility in compound screening. Analyses of sixty-five compounds from the Medicines for Malaria Venture validation and malaria boxes identified 37 compounds with high levels of TRA (>80%); different assay modes allowed discrimination between gametocytocidal and downstream modes of action. Comparison of SMFA data to published assay formats for predicting parasite infectivity indicated that individual in vitro screens show substantial numbers of false negatives. These results highlight the importance of the SMFA in the screening pipeline for transmission reducing compounds and present a rapid and objective method. In addition we present sixteen diverse chemical scaffolds from the malaria box that may serve as a starting point for further discovery and development of malaria transmission blocking drugs.
authors.affiliation: TropIQ Health Sciences, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Martijn W
authors.initials: MW
authors.lastname: Vos
authors.affiliation: Department of Medical Microbiology, Radboud University Nijmegen Medical Center, 6500 HB Nijmegen, The Netherlands.
authors.forename: Will J R
authors.initials: WJ
authors.lastname: Stone
authors.affiliation: TropIQ Health Sciences, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Karin M
authors.initials: KM
authors.lastname: Koolen
authors.affiliation: Department of Medical Microbiology, Radboud University Nijmegen Medical Center, 6500 HB Nijmegen, The Netherlands.
authors.forename: Geert-Jan
authors.initials: GJ
authors.lastname: van Gemert
authors.affiliation: Department of Medical Microbiology, Radboud University Nijmegen Medical Center, 6500 HB Nijmegen, The Netherlands.
authors.forename: Ben
authors.initials: B
authors.lastname: van Schaijk
authors.affiliation: Medicines for Malaria Venture, 20 Route de Pré-Bois, 1215 Geneva 15, Switzerland.
authors.forename: Didier
authors.initials: D
authors.lastname: Leroy
authors.affiliation: TropIQ Health Sciences, PO Box 9101, 6500 HB Nijmegen, The Netherlands.|Department of Medical Microbiology, Radboud University Nijmegen Medical Center, 6500 HB Nijmegen, The Netherlands.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Sauerwein
authors.affiliation: Department of Medical Microbiology, Radboud University Nijmegen Medical Center, 6500 HB Nijmegen, The Netherlands.
authors.forename: Teun
authors.initials: T
authors.lastname: Bousema
authors.affiliation: TropIQ Health Sciences, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Koen J
authors.initials: KJ
authors.lastname: Dechering
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000962:Antimalarials / Q000008:administration & dosage* / Q000737:chemistry; D009033:Culicidae / Q000187:drug effects* / Q000469:parasitology; D055808:Drug Discovery; D049449:Luminescence; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology / Q000635:transmission; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000472:pathogenicity; D054852:Small Molecule Libraries / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D000962:Antimalarials; D054852:Small Molecule Libraries