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Having evolved to produce a myriad of structurally diverse natural products (NPs) as defenses against soil-dwelling parasites including protozoa, Actinomycetota strains are a promising source for the discovery of NPs as antiplasmodial drug leads. Herein, the selective inhibition of P. falciparum is reported for five distinct NP families from Actinomycetota, including an unprecedented family of glycosylated type II polyketides termed sphaeriaurantins (SPAs). The structures of SPAs were established through the combination of MS and NMR spectroscopic data analysis, derivatization and comparison of the deoxyhexose moieties to authentic standards, and quantum chemical calculations, including 1H and 13C NMR chemical shifts and electronic circular dichroism (ECD) spectra. The three isolated SPA congeners reveal that the characteristic pseudodimeric structure of the SPA family of NPs, likely introduced at a late stage of the SPA biosynthesis, is highly relevant for the observed low nanomolar activity. SPA A exhibits a rapid killing profile, with activities across all intraerythrocytic stages, and potent liver stage efficacy, as well as a low propensity for resistance development. Taken together, these results suggest a mode of action that most likely is distinct from the existing antimalarials, supporting SPA A as a promising antimalarial drug lead for further development.<\/jats:p>","DOI":"10.1021\/jacs.6c11333","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T04:03:42Z","timestamp":1786334622000},"page":"35017-35030","source":"Crossref","is-referenced-by-count":0,"title":["Discovery of Sphaeriaurantins\nas Rapid-Acting Antiplasmodials\nwith Dual Activity in Blood and Liver Stages"],"prefix":"10.1021","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3560-7956","authenticated-orcid":true,"given":"Chantal D.","family":"Bader","sequence":"first","affiliation":[{"name":"The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology , , , ,","place":["Jupiter, Florida, United States, 33458"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer E.","family":"Collins","sequence":"additional","affiliation":[{"name":"University of Central Florida , , , ,","place":["Orlando, Florida, United States, 32826"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8650-7344","authenticated-orcid":true,"given":"Yuelan","family":"Li","sequence":"additional","affiliation":[{"name":"The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology , , , ,","place":["Jupiter, Florida, United States, 33458"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Kalkreuter","sequence":"additional","affiliation":[{"name":"The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology , , , ,","place":["Jupiter, Florida, United States, 33458"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasveen","family":"Bhasin","sequence":"additional","affiliation":[{"name":"University of Central Florida , , , ,","place":["Orlando, Florida, United States, 32826"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1886-3878","authenticated-orcid":true,"given":"Mariana Laureano","family":"De Souza","sequence":"additional","affiliation":[{"name":"University of California San Diego , , , ,","place":["La Jolla, California, United States, 92093"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raphaella A.","family":"Paes Lopez","sequence":"additional","affiliation":[{"name":"University of Central Florida , , , ,","place":["Orlando, Florida, United States, 32826"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin H.","family":"Jeon","sequence":"additional","affiliation":[{"name":"Columbia University Irving Medical Center , , , ,","place":["New York, New York, United States, 10032"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nonlawat","family":"Boonyalai","sequence":"additional","affiliation":[{"name":"University of Dundee , , ,","place":["Dundee, U.K., DD14HN"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2945-5856","authenticated-orcid":true,"given":"Chun","family":"Gui","sequence":"additional","affiliation":[{"name":"The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology , , , ,","place":["Jupiter, Florida, United States, 33458"]},{"name":"The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology , , , ,","place":["Jupiter, Florida, United States, 33458"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2917-0663","authenticated-orcid":true,"given":"Dong","family":"Yang","sequence":"additional","affiliation":[{"name":"The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology , , , ,","place":["Jupiter, Florida, United States, 33458"]},{"name":"The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology , , , ,","place":["Jupiter, Florida, United States, 33458"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Fidock","sequence":"additional","affiliation":[{"name":"Columbia University Irving Medical Center , , , ,","place":["New York, New York, United States, 10032"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus C. S.","family":"Lee","sequence":"additional","affiliation":[{"name":"University of Dundee , , ,","place":["Dundee, U.K., DD14HN"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Winzeler","sequence":"additional","affiliation":[{"name":"University of California San Diego , , , ,","place":["La Jolla, California, United States, 92093"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4554-3119","authenticated-orcid":true,"given":"Debopam","family":"Chakrabarti","sequence":"additional","affiliation":[{"name":"University of Central Florida , , , ,","place":["Orlando, Florida, United States, 32826"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9750-5982","authenticated-orcid":true,"given":"Ben","family":"Shen","sequence":"additional","affiliation":[{"name":"The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology , , , ,","place":["Jupiter, Florida, United States, 33458"]},{"name":"The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology , , , ,","place":["Jupiter, Florida, United States, 33458"]},{"name":"The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology , , , ,","place":["Jupiter, Florida, United States, 33458"]},{"name":"Scripps Research , , , ,","place":["Jupiter, Florida, United States, 33458"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,9]]},"reference":[{"key":"2026081910240320400_cit1","volume-title":"World Malaria Report 2023","author":"World-Health-Organization.","year":"2023"},{"key":"2026081910240320400_cit2","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1038\/s41590-020-0648-y","article-title":"Climate change: an\nenduring challenge for vector-borne\ndisease prevention and control","volume":"21","author":"Rocklo\u0308v","year":"2020","journal-title":"Nat. Immunol."},{"key":"2026081910240320400_cit3","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1007\/s40471-021-00266-5","article-title":"Antimalarial drug resistance and\nimplications for the\nWHO global technical strategy","volume":"8","author":"Ippolito","year":"2021","journal-title":"Curr. Epidemiol.\nRep"},{"key":"2026081910240320400_cit4","doi-asserted-by":"publisher","first-page":"1807","DOI":"10.1038\/d41591-024-00028-y","article-title":"Urgent action is needed to confront\nartemisinin partial resistance in African malaria parasites","volume":"30","author":"Ishengoma","year":"2024","journal-title":"Nat. Med."},{"key":"2026081910240320400_cit5","doi-asserted-by":"publisher","first-page":"4538602","DOI":"10.1155\/2020\/4538602","article-title":"Antimalarial\nplants used across Kenyan communities","volume":"2020","author":"Omara","year":"2020","journal-title":"Evid.\nBased Complement Alternat. 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Opinion Biotechnol."},{"key":"2026081910240320400_cit9","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1186\/s12936-019-3026-1","article-title":"Antiplasmodial\nnatural products: an update","volume":"18","author":"Tajuddeen","year":"2019","journal-title":"Malar. J."},{"key":"2026081910240320400_cit10","doi-asserted-by":"publisher","first-page":"84","DOI":"10.4269\/ajtmh.2012.11-0302","article-title":"Development and optimization of a\nnovel 384-well anti-malarial\nimaging assay validated for high-throughput screening","volume":"86","author":"Duffy","year":"2012","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"2026081910240320400_cit11","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1186\/s12936-019-3069-3","article-title":"Antiplasmodial\nprofile of selected compounds from Malaria Box: in vitro evaluation,\nspeed of action and drug combination studies","volume":"18","author":"de Souza","year":"2019","journal-title":"Malar. J."},{"key":"2026081910240320400_cit12","doi-asserted-by":"publisher","first-page":"2433","DOI":"10.1002\/cbic.201500472","article-title":"Gift from\nNature: Cyclomarin A kills Mycobacteria and\nmalaria parasites by distinct modes of action","volume":"16","author":"Bu\u0308rstner","year":"2015","journal-title":"ChemBioChem"},{"key":"2026081910240320400_cit13","doi-asserted-by":"publisher","first-page":"3124","DOI":"10.1128\/AAC.00394-06","article-title":"Tetracyclines specifically target\nthe apicoplast of\nthe malaria parasite Plasmodium falciparum","volume":"50","author":"Dahl","year":"2006","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026081910240320400_cit14","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.29262","article-title":"FDA-approved pharmacotherapy for\nweight loss over the last decade","volume":"14","author":"Idrees","year":"2022","journal-title":"Cureus"},{"key":"2026081910240320400_cit15","doi-asserted-by":"publisher","first-page":"1128","DOI":"10.1093\/tas\/txaa048","article-title":"Determination of\nplasma-chlortetracycline (CTC) concentrations in grazing beef cattle\nfed one of four FDA approved free-choice CTC-medicated minerals","volume":"4","author":"Reppert","year":"2020","journal-title":"Transl. Anim. Sci."},{"key":"2026081910240320400_cit16","doi-asserted-by":"publisher","first-page":"802294","DOI":"10.3389\/fcimb.2021.802294","article-title":"Boromycin has rapid-onset\nantibiotic activity against asexual and sexual blood stages of Plasmodium falciparum","volume":"11","author":"De Carvalho","year":"2022","journal-title":"Front. Cell.\nInfect. Microbiol."},{"key":"2026081910240320400_cit17","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1038\/s41579-019-0306-2","article-title":"Plasmodium asexual\ngrowth and sexual development in the haematopoietic niche of the host","volume":"18","author":"Venugopal","year":"2020","journal-title":"Nat. Rev. Microbiol."},{"key":"2026081910240320400_cit18","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1016\/j.pt.2018.11.010","article-title":"Plasmodium falciparum","volume":"35","author":"Maier","year":"2019","journal-title":"Trends Parasitol."},{"key":"2026081910240320400_cit19","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1016\/j.chom.2013.06.005","article-title":"A microscale\nhuman liver platform that supports the hepatic stages\nof Plasmodium falciparum and vivax","volume":"14","author":"March","year":"2013","journal-title":"Cell Host Microbe"},{"key":"2026081910240320400_cit20","volume-title":"Natural Products Discovery\nCenter Portal","author":"Shen","year":"2022"},{"key":"2026081910240320400_cit21","doi-asserted-by":"publisher","DOI":"10.1101\/2023.12.14.571759","article-title":"The Natural Products Discovery Center: release of the first 8490\nsequenced strains for exploring actinobacteria biosynthetic diversity","volume":"2","author":"Kalkreuter","year":"2024","journal-title":"bioRxiv May"},{"key":"2026081910240320400_cit22","doi-asserted-by":"publisher","first-page":"16567","DOI":"10.1074\/jbc.rev119.006514","article-title":"Leveraging\na large\nmicrobial strain collection for natural product discovery","volume":"294","author":"Steele","year":"2019","journal-title":"J. Biol. Chem."},{"key":"2026081910240320400_cit23","doi-asserted-by":"publisher","first-page":"6265","DOI":"10.1021\/jacsau.5c01236","article-title":"Discovery of 5-chlorotryptophan-containing antibiotics through metabologenomics-assisted\nhigh-throughput screening","volume":"5","author":"Bader","year":"2025","journal-title":"J. Am. Chem. 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Antibiot."},{"key":"2026081910240320400_cit27","doi-asserted-by":"publisher","first-page":"e11131","DOI":"10.1073\/pnas.1716245115","article-title":"Discovery\nof the leinamycin family of natural products by mining actinobacterial\ngenomes","volume":"114","author":"Pan","year":"2017","journal-title":"Proc. Natl. Acad. 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Biochem."},{"key":"2026081910240320400_cit31","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.bcp.2016.11.013","article-title":"Platensimycin\nand platencin: Inspirations\nfor chemistry, biology, enzymology, and medicine","volume":"133","author":"Rudolf","year":"2017","journal-title":"Biochem. pharmacol."},{"key":"2026081910240320400_cit32","doi-asserted-by":"publisher","first-page":"3065","DOI":"10.1021\/acs.molpharmaceut.9b00293","article-title":"Evaluation\nof platensimycin and platensimycin-inspired thioether\nanalogues against methicillin-resistant Staphylococcus aureus in topical and systemic infection mouse models","volume":"16","author":"Su","year":"2019","journal-title":"Mol. 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Rev."},{"key":"2026081910240320400_cit39","doi-asserted-by":"publisher","first-page":"834","DOI":"10.1055\/s-0031-1298432","article-title":"Simultaneous\ndetermination of the absolute configuration of twelve monosaccharide\nenantiomers from natural products in a single injection by a UPLC-UV\/MS\nmethod","volume":"78","author":"Wang","year":"2012","journal-title":"Plant Med."},{"key":"2026081910240320400_cit40","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1248\/cpb.55.899","article-title":"Facile discrimination\nof aldose enantiomers by reversed-phase HPLC","volume":"55","author":"Tanaka","year":"2007","journal-title":"Chem. Pharm. Bull."},{"key":"2026081910240320400_cit42","doi-asserted-by":"publisher","first-page":"8251","DOI":"10.1021\/ja00179a005","article-title":"Efficient implementation\nof the gauge-independent\natomic orbital method for NMR chemical shift calculations","volume":"112","author":"Wolinski","year":"1990","journal-title":"J. Am. Chem. Soc."},{"key":"2026081910240320400_cit43","doi-asserted-by":"publisher","first-page":"12526","DOI":"10.1021\/acs.joc.5b02396","article-title":"Beyond DP4: an improved probability\nfor the stereochemical assignment of isomeric compounds using quantum\nchemical calculations of NMR Shifts","volume":"80","author":"Grimblat","year":"2015","journal-title":"J. Org.\nChem."},{"key":"2026081910240320400_cit44","doi-asserted-by":"publisher","first-page":"12946","DOI":"10.1021\/ja105035r","article-title":"Assigning stereochemistry\nto single diastereoisomers\nby GIAO NMR calculation: the DP4 probability","volume":"132","author":"Smith","year":"2010","journal-title":"J. Am. Chem. Soc."},{"key":"2026081910240320400_cit45","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1002\/chir.22600","article-title":"Good computational\npractice in the assignment of absolute configurations\nby TDDFT calculations of ECD spectra","volume":"28","author":"Pescitelli","year":"2016","journal-title":"Chirality"},{"key":"2026081910240320400_cit46","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1039\/C9NP00002J","article-title":"Applications of OR\/ECD\/VCD to the structure elucidation\nof natural products","volume":"36","author":"Mandi","year":"2019","journal-title":"Nat. Prod. Rep."},{"key":"2026081910240320400_cit47","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.ijpddr.2011.11.001","article-title":"Degrees of chloroquine\nresistance in Plasmodium - is the redox system involved?","volume":"2","author":"Lehane","year":"2012","journal-title":"Int. J. Parasit. 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