title: Identification and deconvolution of cross-resistance signals from antimalarial compounds using multidrug-resistant Plasmodium falciparum strains.
abstract: Plasmodium falciparum, the most deadly agent of malaria, displays a wide variety of resistance mechanisms in the field. The ability of antimalarial compounds in development to overcome these must therefore be carefully evaluated to ensure uncompromised activity against real-life parasites. We report here on the selection and phenotypic as well as genotypic characterization of a panel of sensitive and multidrug-resistant P. falciparum strains that can be used to optimally identify and deconvolute the cross-resistance signals from an extended panel of investigational antimalarials. As a case study, the effectiveness of the selected panel of strains was demonstrated using the 1,2,4-oxadiazole series, a newly identified antimalarial series of compounds with in vitro activity against P. falciparum at nanomolar concentrations. This series of compounds was to be found inactive against several multidrug-resistant strains, and the deconvolution of this signal implicated pfcrt, the genetic determinant of chloroquine resistance. Targeted mode-of-action studies further suggested that this new chemical series might act as falcipain 2 inhibitors, substantiating the suggestion that these compounds have a site of action similar to that of chloroquine but a distinct mode of action. New antimalarials must overcome existing resistance and, ideally, prevent its de novo appearance. The panel of strains reported here, which includes recently collected as well as standard laboratory-adapted field isolates, is able to efficiently detect and precisely characterize cross-resistance and, as such, can contribute to the faster development of new, effective antimalarial drugs.
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Malaria Research Group, New Delhi, India.
authors.forename: Monika
authors.initials: M
authors.lastname: Chugh
authors.affiliation: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Scheurer
authors.affiliation: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Sax
authors.affiliation: Cambridge Systems Biology Center, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Bilsland
authors.affiliation: Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Donelly A
authors.initials: DA
authors.lastname: van Schalkwyk
authors.affiliation: Department of Chemistry, University of Cape Town, Cape Town, South Africa.
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Wicht
authors.affiliation: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland.
authors.forename: Natalie
authors.initials: N
authors.lastname: Hofmann
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Malaria Research Group, New Delhi, India.
authors.forename: Anil
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Syngene International Ltd., Bangalore, India.
authors.forename: Sridevi
authors.initials: S
authors.lastname: Bashyam
authors.affiliation: Syngene International Ltd., Bangalore, India.
authors.forename: Shivendra
authors.initials: S
authors.lastname: Singh
authors.affiliation: Cambridge Systems Biology Center, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Oliver
authors.affiliation: Department of Chemistry, University of Cape Town, Cape Town, South Africa.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Egan
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Malaria Research Group, New Delhi, India.
authors.forename: Pawan
authors.initials: P
authors.lastname: Malhotra
authors.affiliation: Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Sutherland
authors.affiliation: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Beck
authors.affiliation: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland.
authors.forename: Sergio
authors.initials: S
authors.lastname: Wittlin
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Spangenberg
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland xavier.ding@gmail.com.
authors.forename: Xavier C
authors.initials: XC
authors.lastname: Ding
mesh_terms: D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D004351:Drug Resistance / Q000502:physiology; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D000962:Antimalarials