Diversity of antimicrobial peptides and their mechanisms of action. Abstract. Antimicrobial peptides encompass a wide variety of structural motifs. The majority of these peptides are cationic and amphipathic but there are also hydrophobic . There are also antimicrobial peptides which are rich in a certain specific amino acid such as Trp or His. In addition, antimicrobial peptides exist with thio- ether rings, which are lipopeptides or which have macrocyclic Cys knots. In spite of the structural diversity, a common feature of the cationic antimicrobial peptides is that they all have an amphipathic structure which allows them to bind to the membrane interface. Indeed, most antimicrobial peptides interact with membranes and may be cytotoxic as a result of disturbance of the bacterial inner or outer membranes. Alternatively, a necessary but not sufficient property of these peptides may be to be able to pass through the membrane to reach a target inside the cell. The interaction of these peptides with biological membranes is not just a function of the peptide but is also modulated by the lipid components of the membrane. It is not likely that this diverse group of peptides has a single mechanism of action, but interaction of the peptides with membranes is an important requirement for most, if not all, antimicrobial peptides. Antimicrobial peptides encompass a wide variety of structural motifs. The majority of these peptides are cationic and. N.Geetha et al /Int.J.PharmTech Res.2014,6(2),pp 521-529. 522 Previously the crude drugs/extracts prepared from plants were identified by comparison only with the. Antimicrobial Peptides. AMPs are widely distributed throughout nature and have been discovered in certain bacteria, protozoa, fungi, plants, and multicellular. Keywords. Cytotoxic peptide; Peptide- lipid interaction; Membrane permeability; Peptide conformation; Lipopolysaccharide. Introduction. Organisms from throughout the phylogenetic tree, including animals . Many of these substances are peptides. With the growing problem of pathogenic organisms which are resistant to conventional antibiotics, there is increased interest in the pharmacological application of antimicrobial peptides to treat infection. Efforts are currently underway to increase the potency and specificity of these peptides so that they are toxic to microbes and not to mammals. In order to achieve this in an efficient manner, it is important to understand the mechanism of action of these agents and the reason for their selectivity against microbes. Even limiting consideration of antimicrobial agents to peptides, there is still a large variety of structures known. This makes the task for designing improved agents more complex, but at the same time, it provides a range of opportunities for further development. The classification of antimicrobial peptides is somewhat arbitrary and there exist analogs with similar sequences but different conformational motifs which would fall into different classes, despite the similarity of their chemical structure and possibly also of their mechanism of action. Nevertheless, to simplify the problem and to illustrate the range of structures of peptides with antimicrobial activities, we have divided these peptides into groups. These groups include linear peptides which form amphipathic and hydrophobic helices, cyclic peptides and small proteins which form . We will discuss what is known about the structure and the mechanism of action of each of these classes of antimicrobial peptides individually. In general, the mechanism of action of any of these agents is not very well established. For many of these peptides, there is evidence that one of the targets for the peptide is the lipid bilayer of the membrane. Available online a t www.scholarsresearchlibrary.com Scholars Research Library J. Plant Resour., 2012, 2 (1):89-100 (http://scholarsresearchlibrary.com. Antimicrobial peptides (AMPs), also called host defense peptides (HDPs) are part of the innate immune response found among all classes of life. This is because these peptides can often increase the rate of leakage of the internal aqueous contents of liposomes. In addition, most of the antimicrobial peptides are cationic and their interaction with anionic phospholipids would provide a ready explanation for their specificity for bacterial membranes. In Gram- negative bacteria, both the outer leaflet of the plasma membrane as well as the outer membrane contain anionic molecules oriented towards the exterior of the cell. This is not the case for mammalian membranes. Hence, the cationic antimicrobial peptides will preferentially bind to the exposed negative charges of bacterial membranes, but not to the zwitterionic amphiphiles present in the extracellular monolayer of mammalian plasma membranes. This specificity for anionic membrane components is also mimicked in model liposome studies. There is uncertainty, however, about how these peptides perturb the membrane and whether this membrane perturbation is related to the antimicrobial activity of these peptides. It has recently been shown that there is not always a correlation between the ability of peptides to permeabilize membranes and their antimicrobial activity . It is possible that the membrane effects of these peptides are not directly related to their mechanism of cytotoxic action but rather simply the manner by which they enter the cell to reach an alternative target . For example, the amphipathic helical peptide, cecropin, will dissipate a transmembrane electrochemical gradient at a low peptide concentration but requires a higher concentration to affect the release of an encapsulated fluorescent probe . This peptide is cytotoxic to Gram- negative bacteria at low concentrations which dissipate ion gradients but which are not sufficient to cause the release of cytoplasmic contents . Some of these possible mechanisms will be discussed in more detail below. Amphipathic and hydrophobic . However, there are also . Peptides which are not cationic exhibit less selectivity towards microbes compared with mammalian cells. An example of a well- studied hydrophobic and negatively charged cytotoxic peptide is alamethicin. This helical peptide forms clusters of helices that traverse the bilayer and surround an aqueous pore which can transport ions . Another peptide that is hydrophobic and forms a helical transmembrane structure is gramicidin A. In membranes, it forms a cation- selective right- handed helix that traverses the membrane as a single- stranded head- to- head dimer . Both alamethicin and gramicidin are synthesized by microorganisms by a mechanism that does not involve ribosome synthesis. Since these peptides exhibit little selectivity for microbial membranes, their usefulness as specific pharmacological agents is limited. The majority of the cytotoxic amphipathic helical peptides are cationic and they do exhibit selective toxicity for microbes. One of the most studied of the cationic, antimicrobial, amphipathic helical peptides is magainin. This 2. 3 amino acid peptide is secreted on the skin of the African clawed frog, Xenopus laevis. The properties of this peptide have recently been reviewed . From these studies, the concept of a lytic pore has developed. This pore differs in a number of respects from the type of pore formed by helical clusters of peptides, such as that of alamethicin. In the case of magainin, the pore is larger and it does not have discrete open and closed states as conducting pores do. At the same time, the formation of this kind of pore does not result in complete lysis of the membrane. For example, magainin does not allow for the passage of trypsin, a protein of 2. Da . In addition, unlike the alamethicin pore which is lined with only peptide, the wall of the pore formed with magainin contains both lipid and peptide. Evidence for this comes from the fact that magainin stimulates the transbilayer movement of both peptide and lipid. The promotion of positive membrane bilayer curvature would be expected to facilitate the formation of a peptide- and lipid- lined pore and this is what has been found with magainin . However, it has also been observed that the model peptide 1. L, which has a consensus sequence for lytic peptides, promotes negative curvature, as does the wasp venom peptide mastoparan . The cyclic peptide, gramicidin S, promotes the formation of structures which give rise to isotropic 3. P NMR spectra, which may include the formation of inverted cubic phases . At least for zwitterionic membranes, leakage caused by peptides that promote negative curvature is more rapid with bilayers having a negative curvature strain . Current models of the large membrane pores formed by some antimicrobial peptides propose that the pore is lined with both peptide and lipid. The phospholipid in these pores would have a positive curvature and therefore, peptides that facilitated formation of structures with this curvature would facilitate pore formation. However, the mechanism by which peptides promoting negative curvature induce leakage is less well established. It could simply be explained by the pore which is formed being of a small diameter. The dependence of the curvature of a toroidal pore on its diameter is a consequence of the fact that there are two curvatures to consider. One is along the bilayer normal, which predominates in large pores, and the other is in the plane of the bilayer, which is of opposite sign and which predominates in small pores. The importance of the amphipathic helical conformation (Fig. D- isomers resulted in loss of helicity and of antimicrobial activity . However, the importance of an amphipathic helical conformation to the cytotoxic action of peptides was questioned in similar studies with the peptide pardaxin. Pardaxin is an amphipathic helical peptide that shows lytic activity with both microbial and mammalian cells. Incorporation of some D- amino acid residues into pardaxin converts the peptide conformation from an . The modified pardaxin with . Thus, the conformational property of an amphipathic.
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