Discovery of Novel Cyclic Ethers with Synergistic Antiplasmodial Activity in Combination with Valinomycin

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dc.contributor.authorWatson, Daniel J.
dc.contributor.authorMeyers, Paul R.
dc.contributor.authorAcquah, Kojo Sekyi
dc.contributor.authorDziwornu, Godwin A.
dc.contributor.authorBarnett, Christopher Bevan
dc.contributor.authorWiesner, Lubbe
dc.date.accessioned2022-04-05T08:05:41Z
dc.date.available2022-04-05T08:05:41Z
dc.date.issued2021-12-10
dc.date.updated2021-12-23T15:06:56Z
dc.description.abstractWith drug resistance threatening our first line antimalarial treatments, novel chemotherapeutics need to be developed. Ionophores have garnered interest as novel antimalarials due to their theorized ability to target unique systems found in the <i>Plasmodium</i>-infected erythrocyte. In this study, during the bioassay-guided fractionation of the crude extract of <i>Streptomyces</i> strain PR3, a group of cyclodepsipeptides, including valinomycin, and a novel class of cyclic ethers were identified and elucidated. Further study revealed that the ethers were cyclic polypropylene glycol (cPPG) oligomers that had leached into the bacterial culture from an extraction resin. Molecular dynamics analysis suggests that these ethers are able to bind cations such as K<sup>+</sup>, NH<sub>4</sub><sup>+</sup> and Na<sup>+</sup>. Combination studies using the fixed ratio isobologram method revealed that the cPPGs synergistically improved the antiplasmodial activity of valinomycin and reduced its cytotoxicity <i>in vitro</i>. The IC<sub>50</sub> of valinomycin against <i>P. falciparum</i> NF54 improved by 4&ndash;5-fold when valinomycin was combined with the cPPGs. Precisely, it was improved from 3.75 &plusmn; 0.77 ng/mL to 0.90 &plusmn; 0.2 ng/mL and 0.75 &plusmn; 0.08 ng/mL when dosed in the fixed ratios of 3:2 and 2:3 of valinomycin to cPPGs, respectively. Each fixed ratio combination displayed cytotoxicity (IC<sub>50</sub>) against the Chinese Hamster Ovary cell line of 57&ndash;65 &micro;g/mL, which was lower than that of valinomycin (12.4 &micro;g/mL). These results indicate that combinations with these novel ethers may be useful in repurposing valinomycin into a suitable and effective antimalarial.
dc.identifierdoi: 10.3390/molecules26247494
dc.identifier.apacitationWatson, Daniel J., Meyers, Paul R., Acquah, K. S., Dziwornu, Godwin A., Barnett, C. B., & Wiesner, L. (2021). Discovery of Novel Cyclic Ethers with Synergistic Antiplasmodial Activity in Combination with Valinomycin. <i>molecules</i>, 26(24), http://hdl.handle.net/11427/36262en_ZA
dc.identifier.chicagocitationWatson, Daniel J., Paul R. Meyers, Kojo Sekyi Acquah, Godwin A. Dziwornu, Christopher Bevan Barnett, and Lubbe Wiesner "Discovery of Novel Cyclic Ethers with Synergistic Antiplasmodial Activity in Combination with Valinomycin." <i>molecules</i> 26, 24. (2021) http://hdl.handle.net/11427/36262en_ZA
dc.identifier.citationWatson, Daniel J., Meyers, Paul R., Acquah, K.S., Dziwornu, Godwin A., Barnett, C.B. & Wiesner, L. 2021. Discovery of Novel Cyclic Ethers with Synergistic Antiplasmodial Activity in Combination with Valinomycin. <i>molecules.</i> 26(24) http://hdl.handle.net/11427/36262en_ZA
dc.identifier.risTY - Journal Article AU - Watson, Daniel J. AU - Meyers, Paul R. AU - Acquah, Kojo Sekyi AU - Dziwornu, Godwin A. AU - Barnett, Christopher Bevan AU - Wiesner, Lubbe AB - With drug resistance threatening our first line antimalarial treatments, novel chemotherapeutics need to be developed. Ionophores have garnered interest as novel antimalarials due to their theorized ability to target unique systems found in the <i>Plasmodium</i>-infected erythrocyte. In this study, during the bioassay-guided fractionation of the crude extract of <i>Streptomyces</i> strain PR3, a group of cyclodepsipeptides, including valinomycin, and a novel class of cyclic ethers were identified and elucidated. Further study revealed that the ethers were cyclic polypropylene glycol (cPPG) oligomers that had leached into the bacterial culture from an extraction resin. Molecular dynamics analysis suggests that these ethers are able to bind cations such as K<sup>+</sup>, NH<sub>4</sub><sup>+</sup> and Na<sup>+</sup>. Combination studies using the fixed ratio isobologram method revealed that the cPPGs synergistically improved the antiplasmodial activity of valinomycin and reduced its cytotoxicity <i>in vitro</i>. The IC<sub>50</sub> of valinomycin against <i>P. falciparum</i> NF54 improved by 4&ndash;5-fold when valinomycin was combined with the cPPGs. Precisely, it was improved from 3.75 &plusmn; 0.77 ng/mL to 0.90 &plusmn; 0.2 ng/mL and 0.75 &plusmn; 0.08 ng/mL when dosed in the fixed ratios of 3:2 and 2:3 of valinomycin to cPPGs, respectively. Each fixed ratio combination displayed cytotoxicity (IC<sub>50</sub>) against the Chinese Hamster Ovary cell line of 57&ndash;65 &micro;g/mL, which was lower than that of valinomycin (12.4 &micro;g/mL). These results indicate that combinations with these novel ethers may be useful in repurposing valinomycin into a suitable and effective antimalarial. DA - 2021-12-10 DB - OpenUCT DP - University of Cape Town J1 - molecules LK - https://open.uct.ac.za PY - 2021 T1 - Discovery of Novel Cyclic Ethers with Synergistic Antiplasmodial Activity in Combination with Valinomycin TI - Discovery of Novel Cyclic Ethers with Synergistic Antiplasmodial Activity in Combination with Valinomycin UR - http://hdl.handle.net/11427/36262 ER -en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/36262
dc.identifier.urihttps://doi.org/10.3390/molecules26247494
dc.identifier.vancouvercitationWatson Daniel J, Meyers Paul R, Acquah KS, Dziwornu Godwin A, Barnett CB, Wiesner L. Discovery of Novel Cyclic Ethers with Synergistic Antiplasmodial Activity in Combination with Valinomycin. molecules. 2021;26(24) http://hdl.handle.net/11427/36262.en_ZA
dc.publisherMultidisciplinary Digital Publishing Institute
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourcemolecules
dc.source.journalissue24
dc.source.journalvolume26
dc.source.urihttps://www.mdpi.com/journal/molecules
dc.titleDiscovery of Novel Cyclic Ethers with Synergistic Antiplasmodial Activity in Combination with Valinomycin
dc.typeJournal Article
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