Antibiotic peptides

Details Antibiotic peptides Antibiotic peptides

1996-08-27

1999-03-30

Davenport, Avis M.

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

15 to 23 amino acid residues in defined sequence

530327, 530328, 514 13, 514 14, 514 15, 514 16, A61K 3800, C07K 500, C07K 700, C07K 1500

Patent

active

058891480

DESCRIPTION:

BRIEF SUMMARY
This application is a '371 of PCT/KR96/00034 filed Nov. 3,1996.


FIELD OF THE INVENTION

The present invention relates to novel antibiotic peptides which possess superior antibacterial and/or antifungal activities while causing no cytotoxicity, and to antibacterial and/or antifungal agents containing said peptides as active ingredients.


DESCRIPTION OF THE PRIOR ART

More than 100 years have elapsed since the first scientific demonstration of microbial antagonism and five decades since the first clinical use of penicillin. At present, several thousand antibiotics are known and many of them are in practical use. However, studies on the antibiotics have been continuously needed due to the appearance of mutant microorganisms acquired resistance to the antibiotics and the serious side-effects of the commercially available antibiotics. In this regard, attempts to develop novel antibiotics to solve said problems have been carried out by screening secondary metabolites of microorganisms, by synthesizing analogues of known antibiotics such as quinolones or by isolating antibiotics such as proteins or peptides induced by an intracelluar defense mechanism (see Natori S., J. Insect Physiol., 23:1169-1173(1977); Okada M. & Natori S., Biochem. J., 211:727-734(1983); Ando K. et al., Biochemistry, 260:7174-7177(1987); Steiner H. et al., Nature, 292:246-248(1981); Casteels, P. et al., Eur. J. Biochem., 187:381-386(1990)).
On the other hand, it has been known that insects protect themselves from pathogenic bacteria or parasites by their own cellular and humoral immune systems, and they frequently respond to the attack of pathogens by producing antibiotics, e.g., antibacterial proteins or peptides. Until now, about 50 antibacterial proteins or peptides have been isolated from the insects and their structures have been also elucidated. Some of the self-protective proteins or peptides such as Cecropin, have been intensively studied, which provides basic ideas for the development of antibacterial substances whose modes of action are novel.
It has been also reported that most of antibacterial proteins or peptides may target lipid membrane, even though biological activities of all the antibacterial substances are not clearly understood. For example, Cecropin, which is appeared in the hemolymph of certain insects, shows its activity on Gram positive and negative bacteria, by the amphiphilic binding with lipid membrane of bacteria, to form ion channels diverse in size and to allow a rupture of cell membrane(see: Christensen, B. et al., Proc. Natl. Acad. Sci., USA, 85:5072-5076(1988)).
In addition to Cecropin, cysteine-containing Defensin and Sapecin, which are isolated from insects, are fallen within the antibacterial peptides whose target site are lipid membrane of Gram positive bacteria(see: Kuzuhara, T. et al., J. Biochem., 107:514-518(1990)). Their modes of action have been anticipated to be different from Cecropin, in light of the previous finding that insect Defensin leads to bacterial cell lysis in a relatively slower manner than Cecropin which requires only 1 min to reach cell rupture.
Another antibacterial peptides whose target site are lipid membrane, includes Attacin, Sarcotoxin, Deftericin, Coleoptericin, Apidaecin and Abaecin. The peptides conserve G and P domains, and have an influence on the cell differentiation of Gram negative bacteria and, in turn, lead to chain-shaped cell growth. In particular, Attacin has been also reported to break down outer membrane of the targeted bacteria by inhibiting the synthesis of outer membrane proteins.
Besides the antibacterial peptides of insects illustrated as above, several antibiotic peptides have been also isolated from amphibia, e.g., Magainin (see: Zasloff, M., Proc. Natl. Acad. Sci., USA, 84:5449-5453(1987), Ranalexin (see: Clark., D. P. et al., J. Biol. Chem., 269:10849-10855 (1994)), Brevinins (see: Morikawa, N. et al., Biochem. Biophys. Res. Commun., 189:184-190(1992)) and Esculantins (see: Simmaco, M. et al., FEBS Lett., 324:159-161(1993)). The peptides have been kno

REFERENCES:
Gibson, B.W. et al., Novel Peptide Fragments Originating from PGL and the Caerulein and Xenopsin Precursors from Xenopus laevis, J. Biol. Chem., 261(12):5341-5349 (1986).
Lee, J.-Y. et al., Antibacterial Peptides from Pig Intestine: Isolation of a Mammalian Cecropin, Proc. Natl. Acad. Sci., USA86:9159-5162 (1989).
Zasloff, M. et al., Antimicrobial Activity of Synthetic Magainin Peptides and Several Analogues, Proc. Natl. Acad. Sci., USA, 95:910-913 (1988).
Simmaco, M. et al., Antimicrobial Peptides from Skin Secretions of Rana escultenta, J. Biol. Chem., 269(16):11956-11961 (1994).
Zasloff, M. Magainins, a Class of Antimicrobial Peptides from Xenopus Skin: Isolation, Characterization of Two Active Forms, and Partial cDNA Sequence of a Precursor, Proc. Natl. Acad. Sci., USA, 84:5449-5453 (1987).
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Romeo, D. et al., Structure and Bactericidal Activity of an Antibiotic Dodecapeptide Purified from Bovine Neutrophils, J. Biol. Chem., 263(2):9573-9575 (1988).
Steiner, H. et al., Sequence and Specificity of Two Antibacterial Proteins Involved in Insect Immunity, Nature, 292:246-248 (1981).
Matsuyama, K. and Natori, S., Purification of Three Antibacterial Proteins from the Culture Medium of NIH-Sape-4, an Embryonic Cell Line of Sarcophaga peregrina, J. Biol. Chem., 263(32):17112-17116 (1988).
Chopra, I., The Magainins: Antimicrobial Peptides with Potential for topical Application, Journal of Antimicrobial Chemotherapy, 32:351-353 (1993).
Moon, H.J. et al., Purification and Molecular Cloning of cDNA for an Inducible Antibacterial Protein from Larvae of the Coleopteran, Tenebrio molitor, The Journal of Biochemistry, 16(1):53-58 (1994).
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