{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:58:11Z","timestamp":1787029091622,"version":"build-2736575974"},"reference-count":50,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2021,12,10]],"date-time":"2021-12-10T00:00:00Z","timestamp":1639094400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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 Plasmodium-infected erythrocyte. In this study, during the bioassay-guided fractionation of the crude extract of Streptomyces 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+, NH4+ and Na+. Combination studies using the fixed ratio isobologram method revealed that the cPPGs synergistically improved the antiplasmodial activity of valinomycin and reduced its cytotoxicity in vitro. The IC50 of valinomycin against P. falciparum NF54 improved by 4\u20135-fold when valinomycin was combined with the cPPGs. Precisely, it was improved from 3.75 \u00b1 0.77 ng\/mL to 0.90 \u00b1 0.2 ng\/mL and 0.75 \u00b1 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 (IC50) against the Chinese Hamster Ovary cell line of 57\u201365 \u00b5g\/mL, which was lower than that of valinomycin (12.4 \u00b5g\/mL). These results indicate that combinations with these novel ethers may be useful in repurposing valinomycin into a suitable and effective antimalarial.<\/jats:p>","DOI":"10.3390\/molecules26247494","type":"journal-article","created":{"date-parts":[[2021,12,13]],"date-time":"2021-12-13T01:29:33Z","timestamp":1639358973000},"page":"7494","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Discovery of Novel Cyclic Ethers with Synergistic Antiplasmodial Activity in Combination with Valinomycin"],"prefix":"10.3390","volume":"26","author":[{"given":"Daniel J.","family":"Watson","sequence":"first","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town 7700, South Africa"},{"name":"Department of Molecular and Cell Biology, University of Cape Town, Cape Town 7700, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1894-5910","authenticated-orcid":false,"given":"Paul R.","family":"Meyers","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cell Biology, University of Cape Town, Cape Town 7700, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kojo Sekyi","family":"Acquah","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cell Biology, University of Cape Town, Cape Town 7700, South Africa"},{"name":"Department of Chemistry, University of Cape Town, Cape Town 7700, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Godwin A.","family":"Dziwornu","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Cape Town, Cape Town 7700, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher Bevan","family":"Barnett","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Cape Town, Cape Town 7700, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9070-8699","authenticated-orcid":false,"given":"Lubbe","family":"Wiesner","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town 7700, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1504\/IJCBDD.2016.078284","article-title":"Physiology of ionophore transport of potassium and sodium ions across cell membranes: Valinomycin and 18-Crown-6 Ether","volume":"9","author":"Fong","year":"2016","journal-title":"Int. J. Comput. Biol. Drug Des."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2029","DOI":"10.2174\/1568026619666181129125950","article-title":"Ionophores as Potent Anti-malarials: A Miracle in the Making","volume":"18","author":"Bharti","year":"2019","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_3","first-page":"880","article-title":"Antifungal Activity of Valinomycin, a Peptide Antibiotic Produced by Streptomyces sp. Strain M10 Antagonistic to Botrytis Cinerea","volume":"18","author":"Park","year":"2008","journal-title":"J. Microbiol. Biotechnol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Kaushik, V., Yakisich, J.S., Kumar, A., Azad, N., and Iyer, A.K.V. (2018). Ionophores: Potential Use as Anticancer Drugs and Chemosensitizers. Cancers, 10.","DOI":"10.3390\/cancers10100360"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1128\/AAC.36.2.492","article-title":"Inhibitory effects of polyethers on human immunodeficiency virus replication","volume":"36","author":"Nakamura","year":"1992","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1128\/AAC.41.3.523","article-title":"Characterization of the Potent In Vitro and In Vivo Antimalarial Activities of Ionophore Compounds","volume":"41","author":"Gumila","year":"1997","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1128\/AAC.40.3.602","article-title":"Differential In Vitro Activities of Ionophore Compounds against Plasmodium falciparum and Mammalian Cells","volume":"40","author":"Gumila","year":"1996","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1492","DOI":"10.1128\/AAC.01928-15","article-title":"Maduramicin Rapidly Eliminates Malaria Parasites and Potentiates the Gametocytocidal Activity of the Pyrazoleamide PA21A050","volume":"60","author":"Maron","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5521","DOI":"10.1038\/ncomms6521","article-title":"Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum","volume":"5","author":"Vaidya","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"658","DOI":"10.7164\/antibiotics.54.658","article-title":"Potent Antimalarial Activities of Polyether Antibiotic, X-206","volume":"54","author":"Otoguro","year":"2001","journal-title":"J. Antibiot."},{"key":"ref_11","unstructured":"World Health Organization (2021, June 25). World Malaria Report 2020, Available online: https:\/\/www.who.int\/publications\/i\/item\/9789240015791."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1126\/science.358.6360.155","article-title":"Drug-resistant malaria advances in Mekong","volume":"358","author":"Roberts","year":"2017","journal-title":"Science"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2619","DOI":"10.1056\/NEJMc0805011","article-title":"Evidence of artemisinin-resistant malaria in western Cambodia","volume":"359","author":"Noedl","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1016\/j.cell.2016.07.055","article-title":"Malaria: Biology and Disease","volume":"167","author":"Cowman","year":"2016","journal-title":"Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1847","DOI":"10.1016\/0006-2952(94)90582-7","article-title":"Transport pathways in the malaria-infected erythrocyte. Their characterization and their use as potential targets for chemotherapy","volume":"48","author":"Ginsburg","year":"1994","journal-title":"Biochem. Pharmacol."},{"key":"ref_16","unstructured":"Watson, D. (2020). Screening of Actinobacteria for Novel Antimalarial Compounds. [Ph.D. Thesis, University of Cape Town]."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1038\/nbt.3597","article-title":"Sharing and community curation of mass spectrometry data with Global Natural Products Social Molecular Networking","volume":"34","author":"Wang","year":"2016","journal-title":"Nat. Biotechnol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"7785","DOI":"10.1002\/slct.201900922","article-title":"New Cyclodepsipeptide Derivatives Revealed by Genome Mining and Molecular Networking","volume":"4","author":"Paulo","year":"2019","journal-title":"ChemistrySelect"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1038\/s41429-019-0183-y","article-title":"Isolation of depsipeptides and optimization for enhanced production of valinomycin from the North-Western Himalayan cold desert strain Streptomyces lavendulae","volume":"72","author":"Singh","year":"2019","journal-title":"J. Antibiot."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Wibowo, J.T., Kellermann, M.Y., Versluis, D., Putra, M.Y., Murniasih, T., Mohr, K.I., Wink, J., Engelmann, M., Praditya, D.F., and Steinmann, E. (2019). Biotechnological Potential of Bacteria Isolated from the Sea Cucumber Holothuria leucospilota and Stichopus vastus from Lampung, Indonesia. Mar. Drugs, 17.","DOI":"10.3390\/md17110635"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4035","DOI":"10.1038\/s41467-018-06082-8","article-title":"Dereplication of microbial metabolites through database search of mass spectra","volume":"9","author":"Mohimani","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1038\/s41564-017-0094-2","article-title":"Increased diversity of peptidic natural products revealed by modification-tolerant database search of mass spectra","volume":"3","author":"Gurevich","year":"2018","journal-title":"Nat. Microbiol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Wibowo, J., Kellermann, M., K\u00f6ck, M., Putra, M., Murniasih, T., Mohr, K., Wink, J., Praditya, D., Steinmann, E., and Schupp, P. (2021). Anti-Infective and Antiviral Activity of Valinomycin and Its Analogues from a Sea Cucumber-Associated Bacterium, Streptomyces sp. SV 21. Mar. Drugs, 19.","DOI":"10.3390\/md19020081"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Rindelaub, J.D., Baird, Z., Lindner, B.A., and Strantz, A.A. (2019). Identifying extractable profiles from 3D printed medical devices. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0217137"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"110662","DOI":"10.1016\/j.fct.2019.110662","article-title":"Influence of medicinal and aromatic plants into risk assessment of a new bioactive packaging based on polylactic acid (PLA)","volume":"132","author":"Gavril","year":"2019","journal-title":"Food Chem. Toxicol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/0165-1218(92)90006-L","article-title":"Genotoxic potential of crown ethers in mammalian cells: Induction of sister-chromatid exchanges","volume":"280","author":"Arenaz","year":"1992","journal-title":"Mutat. Res. Toxicol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3652","DOI":"10.1007\/s00044-014-0937-9","article-title":"Novel bis-crown ethers and their sodium complexes as antimicrobial agent: Synthesis and spectroscopic characterizations","volume":"23","year":"2014","journal-title":"Med. Chem. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2319","DOI":"10.1002\/jcc.21787","article-title":"MDAnalysis: A toolkit for the analysis of molecular dynamics simulations","volume":"32","author":"Denning","year":"2011","journal-title":"J. Comput. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"VMD: Visual molecular dynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"J. Mol. Graph."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2178","DOI":"10.1021\/acs.jcim.8b00512","article-title":"TTClust: A Versatile Molecular Simulation Trajectory Clustering Program with Graphical Summaries","volume":"58","author":"Tubiana","year":"2018","journal-title":"J. Chem. Inf. Model."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"9181","DOI":"10.3390\/s120709181","article-title":"A unifying review of bioassay-guided fractionation, effect-directed analysis and related techniques","volume":"12","author":"Weller","year":"2012","journal-title":"Sensors"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1039\/C9NP00011A","article-title":"Synergy and antagonism in natural product extracts: When 1 + 1 does not equal 2","volume":"36","author":"Caesar","year":"2019","journal-title":"Nat. Prod. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"PL309","DOI":"10.1016\/S0024-3205(96)00514-0","article-title":"Carboxylic ionophores in malaria chemotherapy: The effects of monensin and nigericin on Plasmodium falciparum in vitro and Plasmodium vinckei petteri in vivo","volume":"59","author":"Adovelande","year":"1996","journal-title":"Life Sci."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Matthews, H., Deakin, J., Rajab, M., Idris-Usman, M., and Nirmalan, N.J. (2017). Investigating antimalarial drug interactions of emetine dihydrochloride hydrate using CalcuSyn-based interactivity calculations. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0173303"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4097","DOI":"10.1128\/AAC.48.11.4097-4102.2004","article-title":"Modified Fixed-Ratio Isobologram Method for Studying In Vitro Interactions between Atovaquone and Proguanil or Dihydroartemisinin against Drug-Resistant Strains of Plasmodium falciparum","volume":"48","author":"Fivelman","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.phymed.2008.12.018","article-title":"Synergy research: Approaching a new generation of phytopharmaceuticals","volume":"16","author":"Wagner","year":"2009","journal-title":"Phytomedicine"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1055\/s-0030-1250736","article-title":"Plant-Based Antimicrobial Studies\u2013Methods and Approaches to Study the Interaction between Natural Products","volume":"77","author":"Viljoen","year":"2011","journal-title":"Planta Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"10012","DOI":"10.1073\/pnas.0403596101","article-title":"Small molecules targeting severe acute respiratory syndrome human coronavirus","volume":"101","author":"Wu","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1038\/nrd1824","article-title":"Opportunities and Challenges in Antiparasitic Drug Discovery","volume":"4","author":"Pink","year":"2005","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"7237","DOI":"10.1038\/s41598-018-25714-z","article-title":"Synergistic combination of two antimicrobial agents closing each other\u2019s mutant selection windows to prevent antimicrobial resistance","volume":"8","author":"Xu","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"11","DOI":"10.3209\/saj.SAJ210102","article-title":"Sphaerosporangium gen. nov., a new member of the family Streptosporangiaceae, with descriptions of three new species as Sphaerosporangium melleum sp. nov., Sphaerosporangium rubeum sp. nov. and Sphaerosporangium cinnabarinum sp. nov., and transfer of Streptosporangium viridialbum Nonomura and Ohara 1960 to Sphaerosporangium viridialbum comb. nov","volume":"21","author":"Ara","year":"2007","journal-title":"Actinomycetologica"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1126\/science.781840","article-title":"Human malaria parasites in continuous culture","volume":"193","author":"Trager","year":"1976","journal-title":"Science"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"739","DOI":"10.4269\/ajtmh.1993.48.739","article-title":"Parasite lactate dehydrogenase as an assay for Plasmodium falciparum drug sensitivity","volume":"48","author":"Makler","year":"1993","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Pluskal, T., Castillo, S., Villar-Briones, A., and Ore\u0161i\u010d, M. (2010). MZmine 2: Modular framework for processing, visualizing, and analyzing mass spectrometry-based molecular profile data. BMC Bioinform., 11.","DOI":"10.1186\/1471-2105-11-395"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1038\/nbt.2377","article-title":"A cross-platform toolkit for mass spectrometry and proteomics","volume":"30","author":"Chambers","year":"2012","journal-title":"Nat. Biotechnol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."},{"key":"ref_47","unstructured":"Case, P.A.K.D.A., Aktulga, H.M., Belfon, K., Ben-Shalom, I.Y., Brozell, S.R., Cerutti, D.S., Cheatham, T.E., Cisneros, G.A., Cruzeiro, V.W.D., and Darden, T.A. (2021, December 09). Amber Tools; San Fran: 2021. Available online: https:\/\/www.researchgate.net\/publication\/37460688_AMBER_10_University_of_California_San_Francisco."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1002\/jcc.20945","article-title":"CHARMM-GUI: A web-based graphical user interface for CHARMM","volume":"29","author":"Jo","year":"2008","journal-title":"J. Comput. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Eastman, P., Swails, J., Chodera, J.D., McGibbon, R.T., Zhao, Y., Beauchamp, K.A., Wang, L.-P., Simmonett, A.C., Harrigan, M.P., and Stern, C.D. (2017). OpenMM 7: Rapid development of high performance algorithms for molecular dynamics. PLoS Comput. Biol., 13.","DOI":"10.1371\/journal.pcbi.1005659"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0022-1759(83)90303-4","article-title":"Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays","volume":"65","author":"Mosmann","year":"1983","journal-title":"J. Immunol. Methods"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/24\/7494\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:45:22Z","timestamp":1760168722000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/24\/7494"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,10]]},"references-count":50,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["molecules26247494"],"URL":"https:\/\/doi.org\/10.3390\/molecules26247494","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,10]]}}}