No. 6] Proc. Jpn. Acad., Ser. B 80 (2004) 245 Review Antiparasitic agents produced by microorganisms ) ),†) By Kazuro SHIOMI* and Satoshi O¯ MURA, M. J. A.** (Contributed by Satoshi O¯ MURA, M. J. A.) Abstract: Microorganisms produce many useful antiparasitic agents. Antiparasitic activities and bio- chemical targets of antiprotozoal and anthelmintic antibiotics are reviewed. Antimalarial apicidin, thiolac- tomycin, fosmidomycin, and borrelidin, antitrypanosomal ascofuranone, and nematocidal emodepside, 2- deoxoparaherquamide A, and nafuredin are recently discovered antibiotics, and they have potential as useful drugs. Key words: Antibiotics; antiparasite; antiprotozoal; anthelmintic. Introduction. Parasites are organisms that range momycin, clindamycin, amphotericin B, trichomycin, from unicellular eukaryotes (protozoa) to multicellular and fumagillin, the anthelmic antibiotics, ivermectin eukaryotes (helminths) (Fig. 1). and paromomycin, and the veterinary nematocidal Many antiparasitic drugs are compounds of natural antibiotics, milbemycin D, destomycin A, and origin or their derivatives. Quinine is an alkaloid hygromycin B. Their activities and the microorganisms derived from the bark of Cinchona spp., and that produce them are summarized in Table I. artemisinin is a sesquiterpene lactone isolated from the In this paper, we review antiparasitic antibiotics pro- Chinese medicinal herb Artemisia annua. Both are duced by microorganisms. In addition to those used as used as antimalarials. α-Santonin is a sesquiterpene antiparasitic antibiotics, we review antibiotics that are isolated from the unexpanded flower heads of under development and new antibiotics that have inter- Artemisia spp., and kainic acid is an amino acid isolated esting activities. from the red alga Digenea simplex. They are used as Antiprotozoals. (a) Antimalarials. Tetracyclines nematocidals. There are also antiparasitic drugs (1, 2, Fig. 2) are broad-spectrum antibacterial agents derived from microorganisms. active against gram-positive and -negative bacteria, Since Alexander Fleming discovered the antibacte- mycoplasmas, rickettsiae, and chlamydiae. They are rial activity of penicillin in 1928, more than 20,000 polyketide antibiotics isolated from culture broths of the antibiotics have been reported.1) Most of them show actinomycetes Streptomyces spp.3)-5) or their semi-syn- antibacterial activity, but some have other interesting thetic derivatives. Tetracyclines are also used as supple- activities, for example, antifungal, antiviral, anticancer, ments to quinine in the treatment of malaria caused by herbicidal, insecticidal, or antiparasitic activities. Plasmodium falciparum, when resistance to quinine Among them, about 600 have been reported to show has been reported in patients and are also effective for antiparasitic activities.2) However, most compounds are prophylaxis of multi-drug resistant P. falciparum.6) cytotoxic, and only a few compounds are used practical- They have potent but slow action against the asexual ly. These include the antiprotozoal antibiotics, tetracy- blood stages of all plasmodial species. They are also clines, polyethers, spiramycin, acetylspiramycin, paro- active against the primary intrahepatic stages of P. fal- ciparum. In addition, tetracyclines have been used to *) School of Pharmaceutical Sciences, Kitasato University, 5-9- treat infections with Entamoeba histolytica, Giardia 1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. ) lamblia, Leishmania major, Trichomonas vagi- ** Kitasato Institute for Life Sciences and Graduate School of 7) Infection Control Sciences, Kitasato University and The Kitasato nalis, and Toxoplasma gondii. Tetracycline treat- Institute, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. ment of filarial nematode-infected animals results in †) Correspondence to: S. O¯ mura. reduced numbers of adult worms and microfilariae, 246 K. SHIOMI and S. O¯ MURA [Vol. 80, Fig. 1. Classification of parasites. Table I. Practically used antiparasitic antibiotics Antibiotics Producing strain Disease Mode of action Antiprotozoals Tetracycline (1) Streptomyces spp. malaria protein synthesis inhibitor Polyethers (10) actinomycetes coccidioisis increase the influx of cations Spiramycin (13) S. ambofaciens cryptosporidiosis protein synthesis inhibitor Acetylspiramycin (14) semisynthetic toxoplasmosis protein synthesis inhibitor Clindamycin (15) semisynthetic toxoplasmosis & babesiosis protein synthesis inhibitor Paromomycin (16) S. rimosus cryptosporidiosis, amebiasis protein synthesis inhibitor & giardiasis Amphotericin B (17) S. nodosus leishmaniasis bind to membrane Trichomycin (19) S. hachijoensis trichomoniasis bind to membrane Fumagillin (21) Aspergillus fumigatus microsporidiasis Met aminopeptidase 2 inhibitor Anthelmintics Ivermectin (24) semisynthetic nematode infections Glu-gated Cl– channel agonist Milbemycin D (29) S. hycroscopicus nematode infections Glu-gated Cl– channel agonist Destomycin A (38) S. rimofaciens nematode infections protein synthesis inhibitor Hygromycin B (39) S. hygroscopicus nematode infections protein synthesis inhibitor Paromomycin (16) S. rimosus cestode infections protein synthesis inhibitor suggesting that tetracyclines may be beneficial for Apicidin (3) is a cyclotetrapeptide produced by the treatment of humans infected with filarial nematodes.8) fungus Fusarium pallidoroseum. It exhibits potent, A chloroplast-like organelle (apicoplast) is present broad-spectrum antiprotozoal activity in vitro against in many species of the phylum Apicomplexa, containing Apicomplexan parasites. It is orally and parenterally Plasmodium, Toxoplasma, Eimeria, and active against P. berghei malaria in mice.11) Its antipara- Cryptosporidium. The organelle is essential for blood- sitic activity appears to be due to low nanomolar inhibi- stage development of Plasmodium and the formation of tion of Apicomplexan histone deacetylase, which the parasitophorous vacuole of Toxoplasma. induces hyperacetylation of histones in treated parasites. Tetracyclines are protein synthesis inhibitors that block Antimalarial activities have also been reported in other binding of aminoacyl-tRNA to the A site of 16S rRNA on peptide antibiotics, such as cyclic peptide the 30S subunit of the prokaryotic ribosome.9) Malarial (takaokamycin),12) cyclic depsipeptides (enniatins),13) parasites have two extrachromosomal DNAs with linear peptides (leucinostatin A 12) and efrapeptins 14)), prokaryotic organelle-like characteristics, apicoplast and peptaibols (antiamebin I and zervamicins).14) and mitochondrial DNA. Tetracyclines are suggested to A thiazole-containing cyclic depsipeptide, inhibit apicoplast and mitochondrial protein synthesis of thiostrepton (4) produced by Streptomyces azureus, Plasmodium.10) eliminates infection with erythrocytic forms of No. 6] Antiparasitic agents produced by microorganisms 247 Fig. 2. Antimalarial antibiotics. Plasmodium berghei in mice. It interacts with the gomyelin and lysocholine phospholipids, and is inhibited GTPase binding domain of the apicoplast large subunit by a mammalian neutral sphingomyelinase inhibitor, rRNA and inhibits protein synthesis, as it does in bacte- scyphostatin (7), produced by the fungus ria.15) Trichopeziza mollissima.19) It also inhibits the It has recently been demonstrated that type II intraerythrocytic proliferation of P. falciparum. fatty acid biosynthesis occurs in the apicoplast, and an Borrelidin (8) is produced by Streptomyces inhibitor of this pathway, thiolactomycin (5), produced spp.,20) and it is a nonglycosidic 18-membered ring by the actinomycete Nocardia sp., restricts the growth macrolide with a side chain of cyclopentanecarboxylic of P. falciparum and Toxoplasma gondii.16) The type II acid. It has various biological activities, such as antimi- pathway is common to plant chloroplasts and bacteria crobial, antiviral, herbicidal, insecticidal, and antitumor but distinct from the type I pathway of mammals. activities. The activities may be due to the inhibition of Furthermore, Trypanosoma brucei, which belongs to threonyl-tRNA synthetase and the activation of cas- the phylum Sarcomastigophora, also uses type II fatty pase-3 and caspase-8.21) Recently, our group found that acid biosynthesis for myristate synthesis, and is suscep- borrelidin shows excellent antimalarial activity against tible to thiolactomycin. both chloroquine-sensitive and -resistant P. falci- In some eubacteria, algae, and plants, the 1-deoxy- parum in vitro.22) It also has antimalarial activity D-xylulose 5-phosphate (DOXP) pathway was against chloroquine-sensitive and -resistant strains in described as an alternative nonmevalonate pathway for mice. The effective dose is lower than that of the early steps in the biosynthesis of isoprenoids. This artemether, artesunate, and chloroquine in each experi- pathway is present in Plasmodium, and its DOXP ment. reductoisomerase is inhibited by fosmidomycin (6) In the same screening, we found that polyether produced by Streptomyces lavendulae.17) Treatment antibiotics have a high selective inhibitory effect with fosmidomycin for acute uncomplicated P. falci- against P. falciparum in vitro. Among these poly- parum infection has been effective in clinical trials.18) ethers, X-206 (9), produced by an actinomycete,23) P. falciparum phospholipase C hydrolyzes sphin- shows the highest selectivity and potency.24) Although, it 248 K. SHIOMI and S. O¯ MURA [Vol. 80, Fig. 3. Anticoccidial, anticryptosporidial, and antitoxoplasmal antibiotics. has potent