Identification and Deconvolution of Antimalarial Compounds Cross-Resistance Signals using Multidrug-Resistant Plasmodium falciparum Strains.


Chugh, M; Scheurer, C; Sax, S; Bilsland, E; van Schalkwyk, DA; Wicht, KJ; Hofmann, N; Sharma, A; Bashyam, S; Singh, S; Oliver, SG; Egan, TJ; Malhotra, P; Sutherland, CJ; Beck, HP; Wittlin, S; Spangenberg, T; Ding, XC; (2015) Identification and Deconvolution of Antimalarial Compounds Cross-Resistance Signals using Multidrug-Resistant Plasmodium falciparum Strains. Antimicrobial agents and chemotherapy, 59 (2). pp. 1110-8. ISSN 0066-4804 DOI: 10.1128/AAC.03265-14

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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.<br/>

Item Type: Article
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Immunology and Infection
Research Centre: Antimicrobial Resistance Centre (AMR)
Malaria Centre
PubMed ID: 25487796
Web of Science ID: 348610000043
URI: http://researchonline.lshtm.ac.uk/id/eprint/2030898

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