Plasmodium knowlesi exhibits distinct in vitro drug susceptibility profiles from those of Plasmodium falciparum
| Autor: | Yee L. Lau, Benjamin Blasco, Jonathan Wee Kent Liew, Didier Leroy, Amirah Amir, Rocio Davina Nuñez, Robert W. Moon, Donelly A. van Schalkwyk, Colin J. Sutherland |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Drug media_common.quotation_subject 030231 tropical medicine Plasmodium falciparum Clone (cell biology) Biology Article lcsh:Infectious and parasitic diseases 03 medical and health sciences Antimalarials 0302 clinical medicine Parasitic Sensitivity Tests parasitic diseases Drug Discovery lcsh:RC109-216 Pharmacology (medical) Plasmodium knowlesi Antimalarial Agent media_common Pharmacology Drug susceptibility Drug discovery biology.organism_classification Virology In vitro Artemisinins 3. Good health Drug Combinations 030104 developmental biology Infectious Diseases Drug development Parasitology Isobolograms |
| Zdroj: | International Journal for Parasitology: Drugs and Drug Resistance International Journal for Parasitology: Drugs and Drug Resistance, Vol 9, Iss, Pp 93-99 (2019) |
| ISSN: | 2211-3207 |
| Popis: | 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. Graphical abstract Image 1 Highlights • P. knowlesi >6-fold less susceptible to several ATP4 inhibitors than P. falciparum. • P. knowlesi equally susceptible to artemisinins and synthetic endoperoxides. • Isobolograms show similar drug interactions for P. knowlesi and P. falciparum. • New P. knowlesi isolate (UM01) similarly susceptible to antimalarials as A1-H.1 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|