Selective and Potent In Vitro Antimalarial Activities Found in Four Microbial Metabolites

Abstract

Antimalarial activities have been identified in four microbial metabolites through a screening programme of existing compounds in the Kitasato Institute chemical library. Hedamycin showed selective and potent activity against both drug-resistant and drug-sensitive strains of Plasmodium falciparum. Simaomicin a exhibited remarkably strong antimalarial activity, although its activity against a drug-resistant strain was weaker than that against a drugsensitive strain. The antimalarial effects of triacsins C and D are also reported. Keywords antimalarialantibiotics, hedamycin, simaomicin a , triacsin, Plasmodium falciparum, drugresistant strain As a result of our on-going program of screening soil microorganisms and renewed testing of compounds lodged in the antibiotic library of the Kitasato Institute for Life Sciences, we have previously reported on various microbial metabolites that exhibit potent antimalarial activities [1ϳ5]. We have now discovered four more compounds that possess antimalarial characteristics. Hedamycin, simaomicin a , triacsin C and triacsin D, all from the antibiotic library of the Kitasato Institute, display potent antimalarial activity in vitro. We report here the antimalarial profiles of these four compounds (Fig. 1) [6ϳ8] in comparison with those of clinically-used antimalarial drugs.In vitro activities against Plasmodium falciparum strains K1 (drug-resistant) and FCR3 (drug-sensitive), and cytotoxicity against human diploid embryonic cell line MRC-5 of these compounds, were measured as described previously [1].Hedamycin showed weak activity against both the K1 and FCR3 strain of P. falciparum, similar to the activity of chloroquine for K1 strain (Table 1). The IC 50 value of chloroquine to the K1 strain is 10-fold higher than to the FCR3 strain, indicating that the antimalarial action of hedamycin is different from that of chloroquine. Although the compound does not meet the UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR) criteria for whole cell screening (IC 50 Ͻ0.1 mg/ml for P. falcipurum K1 strain), it could be a promising lead if the activity could be improved since it has low cytotoxicity (IC 50 Ͼ25 mg/ml).Simaomicin a showed the most potent activity against both drug-resistant K1 and drug-sensitive FCR3. The IC 50 values of the compound were remarkably lower than those of the clinically-used antimalarial drugs, artemether, artemisinin and chloroquine. The cytotoxicity of the compound was weaker (IC 50 ϭ4 ng/ml) than its antimalarial activities. Simaomicin a was 4.6-fold less active against the K1 strain than the FCR3 strain. Although simaomicin a showed considerably more potent antimalarial activity than that of the other compounds, the presence of a polycyclic xanthone structure containing an isoquinoline moiety may

In vitro and in vivo antimalarial activity of puberulic acid and its new analogs, viticolins A–C, produced by Penicillium sp. FKI-4410

“…[3][4][5][6][7][8] Recently, we have isolated some tropolone compounds from a culture broth of Penicillium sp. FKI-4410.…”

Gramicidin S identified as a potent inhibitor for cytochrome bd‐type quinol oxidase

“…From the screening of hundreds of natural antibiotics in the Kitasato Institute for Life Sciences Chemical Library [19], we found the inhibitory activity of GS for Escherichia coli cytochrome bd. Recent studies have shown that GS analogs can be designed with the markedly improved therapeutic index, suggesting the possibility of GS derivatives as potent broad-spectrum antibiotics [9,[20][21][22].…”

Borrelidin, a potent antimalarial: stage-specific inhibition profile of synchronized cultures of Plasmodium falciparum

“…[3][4][5][6][7][8] In the course of our screening, we found borrelidin, produced by an actinomycete strain OM-0060, that proved to be more potent than chloroquine or artemether (using in vivo oral administration) against drug-resistant P. yoelii. 6 The reported biological activities of borrelidin are suggested to be the results of protein synthesis inhibition, caused by the effect on threonyl-tRNA synthetase.…”