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To explore the structural diversity of APD\u2010CLDs, we have identified and prioritized cryptic APD\u2010CLD biosynthetic gene clusters (BGCs) for compound discovery. Using a combination of genetic and chemical methods, we successfully activated three dormant BGCs, leading to the discovery of 12 new APD\u2010CLDs. These newly discovered metabolites significantly expanded the diversity of the APD\u2010CLD family, with chloromalamides and arabimalamides representing the first halogenated and glycosylated members, respectively. Unexpectedly, chloromalamides and arabimalamides exhibited potent antiplasmodial activity, with IC\n                    <jats:sub>50<\/jats:sub>\n                    values in the 25\u2013161\u00a0nM range against drug\u2010sensitive and multidrug\u2010resistant\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    strains. Phenotypic studies revealed arabimalamide B halted parasite development during the asexual blood stage life cycle, resulting in enlarged digestive vacuoles, dispersed hemozoin, and ultimately reduced reinvasion efficiency. These phenotypes are reminiscent of the effect of chloroquine and other 4\u2010aminoquinoline drugs, suggesting that arabimalamides may disrupt the parasite's heme detoxification mechanism. Biosynthetic studies identified key scaffold\u2010forming and modifying enzymes, including a rare membrane glycosyltransferase in arabimalamide biosynthesis. Together, these findings unveil APD\u2010CLDs as new antimalarial lead scaffolds and set the stage for structural diversification and optimization.\n                  <\/jats:p>","DOI":"10.1002\/anie.202523372","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T14:21:23Z","timestamp":1773843683000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Genome\u2010Guided Discovery of Antimalarial 4\u2010Amino\u20102,4\u2010Pentadienoate\u2010Containing Cyclolipodepsipeptides"],"prefix":"10.1002","volume":"65","author":[{"given":"Hartono","family":"Candra","sequence":"first","affiliation":[{"name":"School of Biological Sciences Nanyang Technological University  Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue\u2010Jiao","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Biological Sciences Nanyang Technological University  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