Investigating antimalarial drug interactions of emetine dihydrochloride hydrate using CalcuSyn-based interactivity calculations

Matthews, H; Deakin, J; Rajab, M; Idris-Usman, M; Nirmalan, NJ

Abstract

The widespread introduction of artemisinin-based combination therapy has contributed to
recent reductions in malaria mortality. Combination therapies have a range of advantages,
including synergism, toxicity reduction, and delaying the onset of resistance acquisition.
Unfortunately, antimalarial combination therapy is limited by the depleting repertoire of
effective drugs with distinct target pathways. To fast-track antimalarial drug discovery, we
have previously employed drug-repositioning to identify the anti-amoebic drug, emetine
dihydrochloride hydrate, as a potential candidate for repositioned use against malaria.
Despite its 1000-fold increase in in vitro antimalarial potency (ED50 47 nM) compared with
its anti-amoebic potency (ED50 26±32 uM), practical use of the compound has been limited
by dose-dependent toxicity (emesis and cardiotoxicity). Identification of a synergistic partner
drug would present an opportunity for dose-reduction, thus increasing the therapeutic window.
The lack of reliable and standardised methodology to enable the in vitro definition of
synergistic potential for antimalarials is a major drawback. Here we use isobologram and
combination-index data generated by CalcuSyn software analyses (Biosoft v2.1) to define
drug interactivity in an objective, automated manner. The method, based on the median
effect principle proposed by Chou and Talalay, was initially validated for antimalarial application
using the known synergistic combination (atovaquone-proguanil). The combination was
used to further understand the relationship between SYBR Green viability and cytocidal versus
cytostatic effects of drugs at higher levels of inhibition. We report here the use of the
optimised Chou Talalay method to define synergistic antimalarial drug interactivity between
emetine dihydrochloride hydrate and atovaquone. The novel findings present a potential
route to harness the nanomolar antimalarial efficacy of this affordable natural product.

Citation

Matthews, H., Deakin, J., Rajab, M., Idris-Usman, M., & Nirmalan, N. (2017). Investigating antimalarial drug interactions of emetine dihydrochloride hydrate using CalcuSyn-based interactivity calculations. PLoS ONE, 12(3), e0173303. https://doi.org/10.1371/journal.pone.0173303

• Journal Article Type: Article
• Acceptance Date: Feb 17, 2017
• Publication Date: Mar 3, 2017
• Deposit Date: Mar 30, 2017
• Publicly Available Date: Mar 30, 2017
• Journal: PLOS ONE
• Publisher: Public Library of Science
• Volume: 12
• Issue: 3
• Pages: e0173303
• DOI: https://doi.org/10.1371/journal.pone.0173303
• Publisher URL: https://doi.org/10.1371/journal.pone.0173303
• Related Public URLs: http://www.plosone.org/