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Identification and deconvolution of cross-resistance signals from antimalarial compounds using multidrug-resistant Plasmodium falciparum strains

Chugh, Monika and Scheurer, Christian and Sax, Sibylle and Bilsland, Elizabeth and van Schalkwyk, Donelly A. and Wicht, Kathryn J. and Hofmann, Natalie and Sharma, Anil and Bashyam, Sridevi and Singh, Shivendra and Oliver, Stephen G. and Egan, Timothy J. and Malhotra, Pawan and Sutherland, Colin J. and Beck, Hans-Peter and Wittlin, Sergio and Spangenberg, Thomas and Ding, Xavier C.. (2015) Identification and deconvolution of cross-resistance signals from antimalarial compounds using multidrug-resistant Plasmodium falciparum strains. Antimicrobial agents and chemotherapy, Vol. 59, H. 2. S. 1110-1118.

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Official URL: http://edoc.unibas.ch/dok/A6348522

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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.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Molecular Parasitology and Epidemiology (Beck)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Scheurer, Christian and Wittlin, Sergio and Beck, Hans-Peter
Item Type:Article, refereed
Bibsysno:Link to catalogue
Publisher:American Society for Microbiology
ISSN:0066-4804
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:10 Apr 2015 09:12
Deposited On:10 Apr 2015 09:12

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