van Schalkwyk, Donelly A. and Blasco, Benjamin and Davina Nuñez, Rocio and Liew, Jonathan Wee Kent and Amir, Amirah and Lau, Yee Ling and Leroy, Didier and Moon, Robert W and Sutherland, Colin J. (2019) Plasmodium knowlesi exhibits distinct in vitro drug susceptibility profiles from those of Plasmodium falciparum. International Journal for Parasitology: Drugs and Drug Resistance, 9. pp. 93-99. ISSN 2211-3207, DOI https://doi.org/10.1016/j.ijpddr.2019.02.004.
Full text not available from this repository.Abstract
New antimalarial agents are identified and developed after extensive testing on Plasmodium falciparum parasites that can be grown in vitro. These susceptibility studies are important to inform lead optimisation and support further drug development. Until recently, little was known about the susceptibility of non-falciparum species as these had not been adapted to in vitro culture. The recent culture adaptation of P. knowlesi has therefore offered an opportunity to routinely define the drug susceptibility of this species, which is phylogenetically closer to all other human malarias than is P. falciparum. We compared the in vitro susceptibility of P. knowlesi and P. falciparum to a range of established and novel antimalarial agents under identical assay conditions. We demonstrated that P. knowlesi is significantly less susceptible than P. falciparum to six of the compounds tested; and notably these include three ATP4 inhibitors currently under development as novel antimalarial agents, and one investigational antimalarial, AN13762, which is 67 fold less effective against P. knowlesi. For the other compounds there was a less than two-fold difference in susceptibility between species. We then compared the susceptibility of a recent P. knowlesi isolate, UM01, to that of the well-established, older A1-H.1 clone. This recent isolate showed similar in vitro drug susceptibility to the A1-H.1 clone, supporting the ongoing use of the better characterised clone to further study drug susceptibility. Lastly, we used isobologram analysis to explore the interaction of a selection of drug combinations and showed similar drug interactions across species. The species differences in drug susceptibility reported by us here and previously, support adding in vitro drug screens against P. knowlesi to those using P. falciparum strains to inform new drug discovery and lead optimisation. © 2019 The Authors
| Item Type: | Article |
|---|---|
| Funders: | Medicines for Malaria Venture [grant MMV RD/15/0017], UK Medical Research Council (MRC) Career Development Award [ MR/M021157/1 ] jointly funded by the UK MRC and the UK Department for International Development, Public Health England |
| Uncontrolled Keywords: | Plasmodium falciparum; Plasmodium knowlesi; Drug susceptibility; Isobolograms |
| Subjects: | R Medicine |
| Divisions: | Faculty of Medicine |
| Depositing User: | Ms. Juhaida Abd Rahim |
| Date Deposited: | 05 Dec 2019 08:14 |
| Last Modified: | 05 Dec 2019 08:14 |
| URI: | http://eprints.um.edu.my/id/eprint/23209 |
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