In spite of the fact that the mechanism of action is not satisfactory established for all  cationic peptides, the structural model established by Shai-Matzusaki-Huang  provides a reasonable explanation for most antimicrobial activities of these compounds (Zasloff, 2002). The model proposes that these linear amphipatic-helical peptides  interact with bacterial membranes and increase their permeability, either by the effect of their positive charges with anionic lipids of the target membrane or by membrane destabilization through lipid displacements due to the drastic changes in the net charge of the composed system. A similar mechanism has been proposed for the cysteine-rich peptides such as defensins, which are suggested to form ion-permeable channels in the lipid bilayer. In contrast, some  peptides penetrate into cells to exert their action over target molecules . Several additional hypotheses have been proposed to explain the mechanisms by which peptides kill target cells; such hypotheses include induction of hydrolases which degrade the cell wall, disturbance of membrane functions and damage to crucial intracellular targets after internalization of the peptide .

Anionic peptides: This is a smaller novel group of  molecules displaying antimicrobial activity which, up to now,  have been mostly isolated from mammals.

• Neuropeptide derived molecules:  This is the first class of anionic compounds recently found in infectious exudates of cattle and humans. They mostly include peptides derived from the processing of neuropeptide precursors such as pro-enkephalin-A, to yield active peptide B and enkelytin; some of them are phosphorylated (Salzet and Tasiemsky, 2001). These peptides are mainly active against Gram-positive bacteria at micromolar concentrations, likecationic peptides, and similar products have been reported in some invertebrate species .

• Aspartic-acid-rich molecules: Peptides of this class have been isolated and characterized primarily fromcattle pulmonary surfactants(Brogden et al. 1996; Bals, 2000; Fales-Williams et al. 2002). They have a structure similar to the charge-neutralizing pro-peptides of Group I serine proteases and have been proposed to regulate the activity of pulmonary enzyme systems in these animals. Recently, a novel anionic 47-amino-acid peptide, named dermicidin, has been identified in human sweat, in response to a variety of pathogenic Gram-positive bacteria and ascribed to this class of molecules .

•  Aromatic dipeptides: The aromatic dipeptides comprise low molecular weight antibacterial compounds primarily isolated from dipteran larvae. There areonly two well characterized members: the N--alanyl-5-S-glutathionyl-3,4-dihydroxy-phenylalanine (573 Daltons), identified in the flesh fly  Sarcophaga peregrina (Leem, 1999; Akiyama et al. 2000), and the p-hydroxycinnamaldehyde, isolated from the saw fly Acantholyda parki . The mode of action of these molecules is, at present, unknown.

• Oxygen-binding proteins: Peptides derived from oxygen-binding proteins, or hemocyanin derivatives , are the first representatives of the group of peptides derived from oxygen-binding proteins recently isolated from the hemolymph of arthropods and annelids species. Another molecule, detected in tick hemolymph, is a cleaved form of vertebrate hemoglobin, processed by the parasite after blood meal ingestion . These proteins have been reported as bactericidal compounds and might be considered as a reservoir of defense molecules to be used as integrative weapons to fight pathogens(Vizioli and Salzet, 2002). Bactericidal activity of anionic peptides, oxygen-binding protein derivatives and aromatic dipeptides are not as potent as cationic peptides, and their physiological relevance remains to be established in order to define their importance as components of the innate response .These molecules, whose mode of action could differ from that of cationic peptides and other antibiotics, could complement the  activity of other compounds and constitute a useful base to develop novel synthetic derivatives.

SALZET, M. and TASIEMSKI, A. Involvement of pro-enkephalin-derived peptides in immunity. Developmental and Comparative Immunology, 2001, vol. 25, no. 3, p. 177-185.

BROGDEN, K.; DE LUCCA, A.; BLAND, J. and ELLIOTT, S. Isolation of an ovine pulmonary surfactant-associated anionic peptide bactericidal for Pasteurella haemolytica. Proceeding National Academy of Sciences USA, 1996, vol. 93, no. 1, p. 412-416.

BALS, R. Epithelial antimicrobial peptides in host defence against infection (Review). Respiratory Research, 2000, vol. 1, no. 3, p. 141-150.

FALES-WILLIAMS, A.J.; GALLUP, J.M.; RAMIREZ-ROMERO, R.; BROGDEN, K.A. and ACKERMAN, M.R. Increased anionic peptide distribution and intensity during progression and resolution of bacterial pneumonia. Clinical Diagnostic Laboratory Immunology, 2002, vol. 9, no. 1, p. 28-32.

LEEM, J.Y.; JEONG, I.L.; PARK, K.T. and PARK, H.Y. Isolation of p-hydroxycinnamaldehyde as an antibacterial substance from the saw fly, Acantholyda parki S. FEBS Letters, 1999, vol. 442, no. 1, p. 53-56.

AKIYAMA, N.; HIJIKATA, M.; KOBAYASHI, A.; YAMORI, T.; TSURUO, T. and NATORI, S. Anti-tumor effect of N-beta-alanyl-5-S-glutathionyl dihydroxyphenylalanine (5-S-GAD), a novel anti-bacterial substance from an insect. Anticancer Research, 2000, vol. 20, no. 1A, p. 357-362.

VIZIOLI, J., and SALZET, M. Antimicrobial peptides from animals: focus on invertebrates. Trends in Pharmacological Sciences, 2002, vol. 23, no. 11, p. 494-496.