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Unformatted text preview: A NTIMICROBIAL AGENTS AND CHEMOTHERAPY, 0066-4804/01/$04.00 1 0 DOI: 10.1128/AAC.45.1.145–149.2001 Jan. 2001, p. 145–149 Vol. 45, No. 1 Copyright © 2001, American Society for Microbiology. All Rights Reserved. Antimalarial Activities of Peptide Antibiotics Isolated from Fungi G. NAGARAJ, 1 ² M. V. UMA, 2 M. S. SHIVAYOGI, 1 AND HEMALATHA BALARAM 1 * Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560 064, 1 and Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560 012, 2 India Received 8 May 2000/Returned for modification 13 July 2000/Accepted 12 September 2000 Malaria caused by Plasmodium falciparum is a major public health problem in the developing countries of the world. Clinical treatment of malaria has become complicated due to the occurrence of infections caused by drug resistant parasites. Secondary metabolites from fungi are an attractive source of chemotherapeutic agents. This work reports the isolation and in vitro antiplasmodial activities of peptide antibiotics of fungal origin. The three peptide antibiotics used in this study were efrapeptins, zervamicins, and antiamoebin. The high-performance liquid chromatography-purified peptides were characterized by nuclear magnetic resonance and mass spectral analysis. All three fungal peptides kill P. falciparum in culture with 50% inhibitory concentrations in the micromolar range. A possible mode of action of these peptide antibiotics on P. falciparum is presented. Malaria is a major tropical disease that affects more than 300 million people living in the developing countries of the world (21, 24). The widespread occurrence of drug-resistant Plasmo- dium falciparum infection necessitates the urgent development of new chemotherapeutic agents. Secondary metabolites pro- duced by fungi are often novel molecules with large potential for chemotherapeutic applications. Our aim has been to iso- late, characterize, and screen fungal metabolites for their an- timalarial properties. The secondary metabolites studied in this paper are efrapeptins, zervamicins, and antiamoebin. Table 1 lists the sequences of the peptides used in this study along with the fungal species that produce them. These compounds are peptide antibiotics, 16 amino acids long, that contain the un- usual amino acids a-aminoisobutyric acid, isovaline, b-alanine, and hydroxyproline. Efrapeptins are produced by the fungus Tolypocladium niveum subsp. inflatum and are inhibitors of mitochondrial F F 1 ATPase, some bacterial ATP synthases, and photophosphorylation in plants (1, 13, 14). The ATPase of the protozan parasite Trypanosoma cruzi is also inhibited by efrapeptins (7). Recently, efrapeptins have also been shown to inhibit exocytosis in an ATP-independent manner in eukary- otic cells (22). Both zervamicins and antiamoebin are uncou- plers of mitochondrial oxidative phosphorylation (3, 5, 6, 18)....
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