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Panama bacterium has <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic> anti-<jats:italic>Plasmodium<\/jats:italic> properties. To assess the nature of the <jats:italic>Chromobacterium<\/jats:italic>-produced anti-<jats:italic>Plasmodium<\/jats:italic> factors, chemical partition was conducted by bioassay-guided fractionation where different fractions were assayed for activity against asexual stages of <jats:italic>P. falciparum<\/jats:italic>. The isolated compounds were further partitioned by reversed-phase FPLC followed by size-exclusion chromatography; high resolution UPLC and ESI\/MS data were then collected and revealed that the most active fraction contained a cyclic depsipeptide, which was identified as romidepsin. A pure sample of this FDA-approved HDAC inhibitor allowed us to independently verify this finding, and establish that romidepsin also has potent effect against mosquito stages of the parasite\u2019s life cycle. Genomic comparisons between <jats:italic>C. sp<\/jats:italic>. Panama and multiple species within the <jats:italic>Chromobacterium<\/jats:italic> genus further demonstrated a correlation between presence of the gene cluster responsible for romidepsin production and effective antiplasmodial activity. A romidepsin-null <jats:italic>Chromobacterium spp<\/jats:italic>. mutant loses its anti-<jats:italic>Plasmodium<\/jats:italic> properties by losing the ability to inhibit <jats:italic>P. falciparum<\/jats:italic> HDAC activity, and romidepsin is active against resistant parasites to commonly deployed antimalarials. 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