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 Plasmodium falciparum infection necessitates the urgent development of new chemotherapeutic agents. Secondary metabolites produced by fungi are often novel molecules with large potential for chemotherapeutic applications. Our aim has been to isolate, characterize, and screen fungal metabolites for their antimalarial 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 unusual amino acids ␣-aminoisobutyric acid, isovaline, -alanine, and hydroxyproline. Efrapeptins are produced by the fungus Tolypocladium niveum subsp. inflatum and are inhibitors of mitochondrial F 0 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 eukaryotic cells (22). Both zervamicins and antiamoebin are uncouplers of mitochondrial oxidative phosphorylation (3,5,6,18). Antiamoebin exhibits trypanocidal activity in a mouse model for trypanosomiasis (19) and has been shown to possess anthelmintic properties (30). All three peptide antibiotics also act as channel-forming ionophores (18). Vial et al. have examined numerous other ionophores for antimalarial activity and found gramicidin D to be the most promising candidate under both in vivo and in vitro conditions (11,12). This work reports the purification, spectral characterization, and antimalarial activities of efrapeptins, zervamicins, and antiamoebin. ϩ human blood was prepared in the laboratory. The constituents of the fungal culture medium were obtained from HiMedia Laboratories, Mumbai, India. Silica gel (60 to 80 m) for medium-pressure liquid chromatography (MPLC) was supplied by Büchi Labo...
The Schellman motif is a widely observed helix terminating structural motif in proteins, which is generated when the C‐terminus residue adopts a left‐handed helical (αL) conformation. The resulting hydrogen‐bonding pattern involves the formation of an intramolecular 6 → 1 interaction. This helix terminating motif is readily mimicked in synthetic helical peptides by placing an achiral residue at the penultimate position of the sequence. Thus far, the Schellman motif has been characterized crystallographically only in peptide helices of length 7 residues or greater. The structure of the hexapeptide Boc–Pro–Aib–Gly–Leu–Aib–Leu–OMe in crystals reveal a short helical stretch terminated by a Schellman motif, with the formation of 6 → 1 C‐terminus hydrogen bond. The crystals are in the space group P212121 with a = 18.155(3) Å, b = 18.864(8) Å, c = 11.834(4) Å, and Z = 4 . The final R1 and wR2 values are 7.68 and 14.6%, respectively , for 1524 observed reflections [Fo ≥ 3ς(Fo)]. A 6 → 1 hydrogen bond between Pro(1)CO · · · Leu(6)NH and a 5 → 2 hydrogen bond between Aib(2)CO · · · Aib(5)NH are observed. An analysis of the available oligopeptides having an achiral Aib residue at the penultimate position suggests that chain length and sequence effects may be the other determining factors in formation of Schellman motifs. © 1999 John Wiley & Sons, Inc. Biopoly 50: 13–22, 1999
Efrapeptins are a group of microheterogeneous polypeptide antibiotics produced by the fungus Tolypocladium niveum, which are potent inhibitors of mitochondrial F1-ATPase. Efrapeptins contain an unusual 1,5-diazabicyclo[4:3:0]nonene (DBN) residue at the C-terminus. This study is driven by the hypothesis that the DBN residue could, in principle, arise by oxidative cyclization of a spermidine moiety. Electrospray ionization mass spectrometry of the peptide antibiotics 'elvapeptins' from T niveum establishes the presence of a C-terminal spermidine residue. Conversion of elvapeptins to efrapeptins by CuCl/pyridine demonstrates the transformation of the spermidine residue to the 1,5-diazabicyclo[4:3:0]nonene system by oxidative cyclization.
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