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 X2 and X0ß, which were 4-oxo and 4-hydroxy proline derivatives of actinomycin D, respectively. The former showed an antimalaria activity (IC50 = 0.241 nM) and a cytotoxicity (CC50 = 6.71 nM), while the latter showed IC50 = 7.69 nM and CC50 = 818 nM. Compared with commercially available actinomycin D (IC50 = 0.469 nM and CC50 = 6.71 nM), both actinomycins X2 and X0ß have significant selectivity index (SI) values (CC50/IC50) 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.