Discovery of actinomycin derivatives with improved selectivity against malaria parasites from a Streptomyces culture library

Our group explores the antimalarial compounds from the Streptomyces culture library. Pilot screening showed significant antimalarial activity in Streptomyces antibioticus HUT6035 (synonym of strain NBRC3117). We here isolated antimalarial compounds through large-scale fermentation and subsequent purification using chromatographies. Strain HUT6035 accumulated actinomycins X 2 and X 0ß , which were 4-oxo and 4-hydroxy proline derivatives of actinomycin D, respectively. The former showed an antimalaria activity (IC 50 = 0.241 nM) and a cytotoxicity (CC 50 = 6.71 nM), while the latter showed IC 50 = 7.69 nM and CC 50 = 818 nM. Compared with commercially available actinomycin D (IC 50 = 0.469 nM and CC 50 = 6.71 nM), both actinomycins X 2 and X 0ß have significant selectivity index (SI) values (CC 50 /IC 50 ) with 27.9 and 106. These SI values were two- and seven-fold preferential against that of actinomycin D (SI = 14.3). Thus, actinomycin derivatives are potential antimalarial agents.