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References

8 Kunz, 1). A., Reddy, G. S. and Vatvarc, A. (1985) App l. Errvivon.Mitn~ brol. 50, X31-836

9 Bruce, N . C., Wilma. C. J., Jordan, K. N., Trrbilcock, A. E.,Gray Ste phem. L. D. and Lowe, C. R. (1990) flrc/l . Miuobiol. 154,465-470

10 Hail% A. M. and Bruce, N. C. (1993) Appi Ewnvr. .\/i~-mhiol. 59,2166-2170

11 Bruce, N. C., Wilmot, C. J., Jordan, K. N., Gray Stcphem , L. D. andLowe, C. R. (1991) Bio&m .J. 274, 875Gi80

12 Bruce, N. C., Caswell, D. A., French, C. E., H&s, A. M., Long,M. 1. and Willey, D. L. (1994) A t~n. 1vYAciul. Sti. 721, 85-100

13 Cameron, 2. W. W., Jordxl, K. N., Holt, P. J,, Raker, 1. B.,Lowe, C. 11. and Bruce, N. C. (1994) App l. Ewirorr. ~!&mh iul.60,3881-3883

14 Holt, 1. J., Gray Stephens, L. I)., Bruce, N. C. and Lowe, C. R.Riosors. Bioclecrm. m press)

15 Rathbonr, D. A., Holt, 1. J., Bruce, N. C. and Lowe, C. R. .4rwihiY Atud. &I. (III j


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Xenopus laevisMagaininiPGSPGLaXPFBombina speciesBombininBombtnin HPhyllomedusa speciesDermaseptinAdenoregulinLitoria speciesCaerin-1.1Caeridin-1Rana speciesBrevinin-1Brevinln-l EGaegurin-6RanalexinBrevinin-2Brevinin-2EGaegurin-2

Figure 1Amino acid sequence s of antimicroblal peptldes from different amphibian specie s.Representative members of the different peptide families are presented: peptldyl-glyclne-senne (PGS); peptldyl-glyclne-leucine carboxyamide (PGLa); xenopsin precur-sor fragment (XPF). Amidated C-terminal residues are represented by d; o-alloisoleuc ineis represented by 1*. The bars represent disulphlde bridges.

dif ferent amphibian species were studied in moredetail. The production ofantimicrobial peptides is partof the innate immune system and is widespread inNature,. This system was firs t discovered in insecthaemolymph when the synthesis of antimicrobial pep-tides, such as cecropins and dofensins, is induced inresponse to lllicrobial infection. A similar systenl wassubsequently shown to operate in the lung and gastro-intestinal tract of nlanmlals; indeed, the system showsstriking similarities to the vertebrate acute-phaseimnunc response. In alnphibians, the production ofantinlicrobial pcptides appears to be constitutivc, butthey are released in response to an external stimulus;this is probably mediated by epinephrine. Althoughthis innate immunity lacks the memory and speci-fic ity of acquired inumunity based on itmmunoglobu-lins directed against specif ic antigens, it has at least twoadvantages: the peptides are inimediately availablefront a reservoir in the cutaneous granular glands, andthey usually have act ivi ty against a broad spectrunz ofniici-oorgaliisiiis.

So far, relative ly few frog species from a limitednumber of fanlilies have been studied. While all the

antinlicrobial skin peptides studied to date are cationic,it is already clear that large differences exist in featuressuch as size, the prcscnce of disulphide bonds, andother structural niotifs .Mechanism of action

A large nunlber of antimicrobial peptides frormaniphibian skin can adopt an anlphipathic a-helicalstructure in hydrophobic environments, suggestingthat oligomers ofsuch helices would forni pores in thephospholipid bilayer of target niembranes. Inhibitionof cell growth and cell death may then result frorm thedisturbance of rnenlbrane functions. This hypothesisis confirmed by the results of experiments perfonledwith synthetic peptides containing only I)-amino acids:an amphipathic left-handed a-helix is fornled, but thebiological act ivi ty of the natural I counterpart isretained. Therefore, an interaction with chiral bind-ing sites of receptors, enzynles or other melnbrancproteins can be ruled out. The select ivity of sonle ofthese peptides for bacterial membranes rmay be relatedto the number, and distribution, of positive charges. Itis known that bacterial nienibranes contain higheranlounts of anionic phospholipids than the erythro-cyte niembrane, for example. However, nluch less isknown about the mechanisnl by which other types ofantimicrobial peptides, which do not fornl amph-pathic helices, inhibit cell growth or cause cell death.The interaction of peptides sucl~ as bornbinin H andbrevinil l-IE (Fig. 1) with bacterial and niodel men-branes reniains to be investigated.Peptide structure and antimicrobial act ivit y

In recent years, antinlicrobial peptides have beenisolated and characterized front the skin of Xerro~~rrsIacv is, Bmbirra varicpfa and B. wimtali~, W~yl1orrrc~1rr.wralrqri and I? h/w, Litovia spkrdida and L. cacvrrlcn,and several species o f Rorritlac~. In the original studieson X. lawis, the skin secretion was investigated in greatdetail, and was found to contain the magainins/pep-tidyl-glycine-scrine (PGS) peptides,, peptidyl-glycine-leucine carboxyarnide (PGLa), and a multi-tude of fragments derived from the precursors of,among others, caerulein, xenopsin and laevitide.These peptides, each of which contains nlore than 20anlino acids, and can form amphipathic helices, havea broad spectrum of antimicrobial act ivi ty againstGrant-positive and Gram-negative bacteria, fungi andprotozoa 1 . In addition, Imixtures of these peptidesshow strong synergistic effect s, which lead toan enhancement of the antimicrobial action of thesecretion.

Two different families of skin peptides from Bornbinaspecies have been described: the bonibinins, andthe type H bombinins 14. The bombinins are a groupof antibacterial peptides with identical C-terminalsequences, but with variable N-terminal sequencesrelated to the original bonlbinin4,,. Type Hbonlbinins are Imore hydrophobic molecules, possess-ing both antibacterial and haernolytic activities1z-4.Surprisingly, it was found that sonle type H bonibinin

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barra and simmaco

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