The magainins: antimicrobial peptides with potential for topical application

Recently a number of endogenous host defence molecules with antimicrobial activity have been identified in mammals, invertebrates and amphibians (for reviews see Ganz, Selsted Within this group of anti-microbial agents there are several small peptides (2-4K.) that include the defensins (found predominantly in mammalian phago-cytes), cecropins, diptericins, attacins, apidae-cins, abaecin, royalisin (all from insect sources) and the magainins (amphibian source). A number of semi-synthetic magainins are currently under development as topical anti-microbial agents with potential dermatolo-gical, ophthalmic and periodontal applications (Anonymous, 1992). This article briefly reviews the current status of the magainins, and considers the structure, mode of action and antimicrobial spectrum of these peptides. Amongst the defensins, the magainins (or magainin analogues) are the most advanced in terms of commercial development (Rennie, 1993). It is for this reason that this article focuses on the magainins since they have a greater chance of reaching the clinic than do other host defence peptides. Magainins were identified in the skin secretions of the African clawed frog, Xenopus laevis, by Zasloff and co-workers (Zasloff, 1987; Zasloff, Martin & Chen, 1988). These host defense peptides are secreted by granular glands in the skin of the frog in response to tissue injury (MacDonald, Berkowitz & Jacob, 1990). Magainins 1 and 2 (mgn 1 and 2) (also known as PGS-peptides beginning with glycine and ending with serine) are 23 residue peptides with the following sequences (Zasloff el al., (peptide beginning with glycine and ending with leucine amide), is another antimicrobial peptide (21 residues) isolated from frog skin (Williams et al. Little sequence homology with mgnl or mgn2 these peptides are all positively charged and can form amphiphilic helices about 30 A in length (Williams et al., 1990). Because these features are common to polypeptides that bind to lipid bilayers it has been suggested that magainins and PGLa act as transmembrane helical channel former that dissipate the membrane potential (Zasloff, 1987). Subsequent membrane depolarization studies in Escherichia coli using tetraphenyl phosphonium ion (TPP +) to measure the membrane potential have indeed confirmed that mgn2 and PGLa dissipate the membrane potential (Westerhoff et al., 1989; Jurectic, 1990). Although mgnl was not specifically examined in these studies (Westerhoff et al., 1989; Jurectic, 1990) its structural similarity to mgn2 implies a similar mode of action. Antimicrobial agents that dissipate the membrane potential invariably have secondary effects on bacterial metabolism leading to stimulation of autolytic enzyme activity, bacterial lysis and cell …