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Sir: In the course of our screening program to discover antimalarial antibiotics from soil microorganisms which are active against drug-resistant parasites in vitro and in vivo, we previously reported that the polyether antibiotics X-206 and K-41 and other microbial metabolites exhibited potent antimalarial properties1-3). Thereafter, we found that a substance produced by an actinomycete strain OM-0060 had potent and selective antimalarial activities in vitro and in vivo. It was identified as borrelidin, a known nonglycosidic 18-membered macrolide antibiotic with a cyclopentanecarboxylic acid side chain (Fig. 1)4,5). We report here the antimalarial profile of borrelidin in comparison with those of clinically used antimalarial drugs. Borrelidin was isolated from the cultured broth of an actinomycete strain OM-0060. In vitro activities against Plasmodium falciparum strains K1 (drug-resistant) and FCR3 (drug-sensitive), and cytotoxicity against human diploid embryonic cell line MRC-5 were measured as described previously1). Rodent malaria-derived strains for in vivo 4-days suppressive testing, P. berghei N (drugsensitive) and P. yoelii ssp. NS (chloroquine-resistant) were used to assess in vivo antimalarial activities as described previously1,2). Test compounds were dissolved in 10% DMSO-Tween 80 aqueous solution and administered subcutaneously (s.c.) or orally (p.o.) to the mice two hours after infection with parasites (Day 0). Then the compounds were successively administered (s.c. or p.o.) to the infected mice once a day for 3 days (Days 1-3). On the day after the last treatment (Day 4), thin blood films were made from the tail blood of the mice, and the parasitaemia was determined as described previously2). Table 1 shows the in vitro antimalarial activities of borrelidin and the standard antimalarial drugs. Borrelidin showed more potent activity against the drug-resistant K1 strain of P. falciparum than the clinically used antimalarials, artemether, artesunate and chloroquine. Furthermore, borrelidin showed similar activity against the drug-sensitive FCR3 strain of P. falciparum to artemether and artesunate, and was more potent than chloroquine. The cytotoxicity of borrelidin against MRC-5 cells was relatively low (the IC50 value: 410nM). Borrelidin showed high selectivity indexes with the ratios of 216 and 228 for the MRC-5 cells/K1 strain and MRC-5 cells/FCR3 strain, respectively. Table 2 shows a preliminary comparison of the in vivo subcutaneous antimalarial activities of borrelidin and the standard antimalarial drugs. Borrelidin had antimalarial activity against both rodent malaria-derived P. berghei N and P. yoelii ssp. NS. Especially, borrelidin showed more potent subcutaneous antimalarial effects than artemether, artesunate and chloroquine against the chloroquine resistant strain (P. yoelii ssp. NS). The ED50 and ED90 values of borrelidin against P. yoelii ssp. NS were lower by factors 5.7-64 and 6.4->125, respectively, than those of the other three drugs. Borrelidin also showed more potent

journal of antibiotics

In Vitro and in Vivo Antimalarial Activities of a Non-glycosidic 18-Membered Macrolide Antibiotic, Borrelidin, against Drug-resistant Strains of Plasmodia