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Emerging parasitic drug resistance places an urgent need to explore chemotherapies with novel structures and mechanisms of action. Natural products have historically provided effective antimalarial drug scaffolds. In an effort to search nature's chemical potential for antiplasmodial agents, unconventionally sourced organisms coupled with innovative cultivation techniques were utilized. Approximately 60,000 niche microbes from various habitats (slow\u2010growing terrestrial fungi, Antarctic microbes, and mangrove endophytes) were cultivated on a small\u2010scale, extracted, and used in high\u2010throughput screening to determine antimalarial activity. About 1% of crude extracts were considered active and 6% partially active (\u226567% inhibition at 5 and 50 \u03bcg\/mL, respectively). Active extracts (685) were cultivated on a large\u2010scale, fractionated, and screened for both antimalarial activity and cytotoxicity. High interest fractions (397) with an IC<jats:sub>50<\/jats:sub> &lt; 1.11 \u03bcg\/mL were identified and subjected to chromatographic separation for compound characterization and dereplication. Identifying active compounds with nanomolar antimalarial activity coupled with a selectivity index tenfold higher was accomplished with two of the 52 compounds isolated. This microscale, high\u2010throughput screening project for antiplasmodial agents is discussed in the context of current natural product drug discovery efforts.<\/jats:p>","DOI":"10.1002\/med.21335","type":"journal-article","created":{"date-parts":[[2014,12,26]],"date-time":"2014-12-26T08:18:48Z","timestamp":1419581928000},"page":"144-168","source":"Crossref","is-referenced-by-count":7,"title":["Miniaturized Cultivation of Microbiota for Antimalarial Drug Discovery"],"prefix":"10.1002","volume":"36","author":[{"given":"Carrie","family":"Waterman","sequence":"first","affiliation":[{"name":"Department of Chemistry University of South Florida  Tampa Florida 33620 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laurent","family":"Calcul","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of South Florida  Tampa Florida 33620 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