Antimicrobial peptides

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Antimicrobial peptides (also called host defence peptides) are an evolutionarily conserved component of the innate immune response and are found among all classes of life. Fundamental differences exist between prokaryotic and eukaryotic cells that may represent targets for antimicrobial peptides. These peptides are potent, broad spectrum antibiotics which demonstrate potential as novel therapeutic agents. Antimicrobial peptides have been demonstrated to kill Gram negative and Gram positive bacteria (including strains that are resistant to conventional antibiotics), mycobacteria (including Mycobacterium tuberculosis), enveloped viruses, fungi and even transformed or cancerous cells [1] Unlike the majority of conventional antibiotics it appears as though antimicrobial peptides may also have the ability to enhance immunity by functioning as immunomodulators.

Contents

[edit] Structure

Various structures of antimicrobial peptides

Antimicrobial peptides are a unique and diverse group of molecules, which are divided into subgroups on the basis of their amino acid composition and structure.[2] Antimicrobial peptides are generally between 12 and 50 amino acids. These peptides include two or more positively charged residues provided by arginine, lysine or, in acidic environments, histidine, and a large proportion (generally >50%) of hydrophobic residues.[3][4][5] The secondary structures of these molecules follow 4 themes, including i) α-helical, ii) β-stranded due to the presence of 2 or more disulfide bonds, iii) β-hairpin or loop due to the presence of a single disulfide bond and/or cyclization of the peptide chain, and iv) extended.[6] Many of these peptides are unstructured in free solution, and fold into their final configuration upon partitioning into biological membranes. It contain hydrophilic amino acid residues aligned along one side and hydrophobic amino acid residues aligned along the opposite side of a helical molecule.[2] This amphipathicity of the antimicrobial peptides allows to partition into the membrane lipid bilayer. The ability to associate with membranes is a definitive feature of antimicrobial peptides[7] although membrane permeabilisation is not necessary. These peptides have a variety of antimicrobial activities ranging from membrane permeabilization to action on a range of cytoplasmic targets.

Type characteristic AMPs
Anionic peptides rich in glutamic and aspartic acids Maximin H5 from amphibians, Dermcidin from humans
Linear cationic α-helical peptides lack in cysteine Cecropins, andropin, moricin, ceratotoxin and melittin from insects, Magainin, dermaseptin, bombinin, brevinin-1,esculentins and buforin II from amphibians, CAP18 from rabbits, LL37 from humans
Catioinic peptide enriched for specific amino acid rich in proline, arginine, phenylalanine, glycine, tryptophan abaecin, apidaecins from honeybees, prophenin from pigs, indolicidin from cattle.
Anionic and cationic peptides that contain cysteine and form disulfide bonds contain 1~3 disulphide bond 1 bond:brevinins, 2 bonds:protegrin from pig, tachyplesins from horseshoe crabs, 3 bonds:defensins from humans, more than 3:drosomycin in fruit flies
The modes of action by Antimicrobial peptides

[edit] Antimicrobial Activities

The modes of action by which antimicrobial peptides kill bacteria is varied and includes disrupting membranes, interfering with metabolism, and targeting cytoplasmic components. The initial contact between the peptide and the target organism would be electrostatic, as most bacterial surface are anionic. Their amino acid composition, amphipathicity, cationic charge and size allow them to attach to and insert into membrane bilayers to form pores by ‘barrel-stave’, ‘carpet’ or ‘toroidal-pore’ mechanisms. Or allow them to penetrate into the cell to bind intracellular molecules which are crucial to cell living.[8] Intracellular binding model includes inhibition of cell wall synthesis, alteration of cytoplasmic membrane, activation of autolysin, inhibition of DNA, RNA, and protein synthesis, and inhibition of certain enzymes. However, in many cases, the exact mechanism of killing is not known. In contrast to many conventional antibiotics these peptides appear to be bacteriocidal (bacteria killer) instead of bacteriostatic (bacteria growth inhibitor). In general the antimicrobial activity of these peptides is determined by measuring the minimal inhibitory concentration (MIC), which is the lowest concentration of drug that reduces growth by more than 50%.[9]

[edit] Immunomodulatory Activities

In addition to killing bacteria directly they have been demonstrated to have a number of immunomodulatory functions that may be involved in the clearance of infection, including the ability to alter host gene expression, act as chemokines and/or induce chemokine production, inhibiting lipopolysaccharide induced pro-inflammatory cytokine production, promoting wound healing, and modulating the responses of dendritic cells and cells of the adaptive immune response. Animal models indicate that host defence peptides are crucial for both prevention and clearance of infection. It appears as though many peptides initially isolated as and termed “antimicrobial peptides” have been shown to have more significant alternative functions in vivo (e.g. hepcidin[10]).

[edit] Determination of AMP action

Several methods have been used to determine the mechanisms of antimicrobial peptide activity.[8]

Methods Applications
Microscopy to visualize the effects of antimicrobial peptides on microbial cells.
Fluorescent dyes to measure antimicrobial peptides to permeabilize membrane vesicles.
Ion channel formation to assess the formation and stability of an antimicrobial-peptide-induced pore.
Circular dichroism and orientated circular dichroism to measure the orientation and secondary structure of an antimicrobial peptide bound to a lipid bilayer
Solid-state NMR spectroscopy to measure the secondary structure, orientation and penetration of antimicrobial peptides into lipid bilayers in the biologically relevant LIQUID-CRYSTALLINE STATE
Neutron diffraction to measure the diffraction patterns of peptide-induced pores within membranes in oriented multilayers or liquids

[edit] Therapeutic Potential

These peptides are excellent candidates for development as novel therapeutic agents and complements to conventional antibiotic therapy because in contrast to conventional antibiotics they do not appear to induce antibiotic resistance while they generally have a broad range of activity, are bacteriocidal as opposed to bacteriostatic and require a short contact time to induce killing. A number of naturally occurring peptides and their derivatives have been developed as novel anti-infective therapies for conditions as diverse as oral mucositis, lung infections associated with cystic fibrosis (CF), cancer,[11] and topical skin infections. Pexiganan has been shown to be useful to treat infection related diabetic foot ulcer.

[edit] Models of Antimicrobial Peptides

Computer simulations have recently provided atomistic resolution pictures of how antimicrobial peptides interact with membranes.[12][13] Biophysical studies utilizing solid-state NMR experiments have provided an atomic-level resolution explanation of membrane disruption by antimicrobial peptides.[14][15]

[edit] Selectivity of antimicrobial peptides

In the competition of bacterial cells and host cells with the antimicrobial peptides, antimicrobial peptides will preferentially interact with the bacterial cell to the mammalian cells, which enables them to kill microorganisms without being significantly toxic to mammalian cells.[16] Selectivity is a very important feature of the antimicrobial peptides and it can guarantee their function as antibiotics in host defense systems.

[edit] Factors that determine the selectivity of antimicrobial peptides

There are some factors that are closely related to the selectivity property of antimicrobial peptides, among which the cationic property contributes most. Since the surface of the bacterial membranes is more negatively charged than mammalian cells, antimicrobial peptides will show different affinities towards the bacterial membranes and mammalian cell membranes.[17]

In addition, there are also other factors that will affect the selectivity. It’s well known that cholesterol is normally widely distributed in the mammalian cell membranes as a membrane stabilizing agents but absent in bacterial cell membranes; and the presence of these cholesterols will also generally reduce the activities of the antimicrobial peptides, due either to stabilization of the lipid bilayer or to interactions between cholesterol and the peptide. So the cholesterol in mammalian cells will protect the cells from attack by the antimicrobial peptides.[18]

Besides, the transmembrane potential is well-known to affect peptide-lipid interactions.[19] There's an inside-negative transmembrane potential existing from the outer leaflet to the inner leaflet of the cell membranes and this inside-negative transmembrane potential will facilitate membrane permeabilization probably by facilitating the insertion of positively charged peptides into membranes. By comparison, the transmembrane potential of bacterial cells is more negative than that of normal mammalian cells, so bacterial membrane will be prone to be attacked by the positively charged antimicrobial peptides.

Similarly, it is also believed that increasing ionic strength,[18] which in general reduces the activity of most antimicrobial peptides, contributes partially to the selectivity of the antimicrobial peptides by weakening the electrostatic interactions required for the initial interaction.

Molecular Basis of Cell Selectivity of Antimicrobial Peptides

[edit] Mechanism of the selectivity

The cell membranes of bacterial are rich in acidic phospholipids, such as phosphatidylglycerol and cardiolipin.[16][20] These phospholipid headgroups are heavily negatively charged. Therefore, the outmost leaflets of the bilayer which is exposed to the outside of the bacterial membranes are more attractive to the attack of the positively charged antimicrobial peptides. So the interaction between the positive charges of antimicrobial peptides and the negatively charged bacterial membranes is mainly the electrostatic interactions, which is the major driving force for cellular association. Besides, since antimicrobial peptides form structures with a positively charged face as well as a hydrophobic face, there are also some hydrophobic interactions between the hydrophobic regions of the antimicrobial peptides and the zwitterionic phospholipids (electrically neutral) surface of the bacterial membranes, which act only as a minor effect in this case.

In contrast, the outer part of the membranes of the plants and mammals is mainly composed of lipid without any net charges since most of the lipids with negatively charged headgroups are principally sequestered into the inner leaflet of the plasma membranes.[17] Thus in the case of mammals cells, the outer surfaces of the membranes are usually made of zwitterionic phosphatidylcholine and sphingomyelin, even though a small portion of the membranes outer surfaces contain some negatively charged gangliosides. So the hydrophobic interaction between the hydrophobic face of amphipathic antimicrobial peptides and the zwitterionic phospholipids on the cell surface of mammalian cell membranes plays a major role in the formation of peptide-cell binding.[21] However, the hydrophobic interaction is relatively weak when compared to the electrostatic interaction, thus, the antimicrobial peptides will preferential interact with the bacterial membranes.

Dual polarisation interferometry has been used in vitro to study and quantify the association to headgroup, insertion into the bilayer, pore formation and eventual disruption of the membrane.[22][23]

[edit] Methods to control the selectivity of antimicrobial peptides

A lot of efforts have been tried to control the cell selectivities. For example, Katsumi tried to modify and optimize the physicochemical parameters of the peptides to control the selectivities, including net charge, helicity, hydrophobicity per residue (H), hydrophobic moment (μ) and the angle subtended by the positively charged polar helix face (Φ).[19] Besides, other methods like the introduction of D-amino acids and fluorinated amino acids in the hydrophobic face is believed to break the secondary structures and thus to reduce hydrophobic interaction that’s necessary for interaction with mammalian cells. Wan L Z, el[citation needed] also found that Pro→Nlys substitution in Pro-containing β-turn antimicrobial peptides is a promising strategy for the design of new short bacterial cell-selective antimicrobial peptides with intracellular mechanisms of action. Nadezhda V el[citation needed] suggested that direct attachment of magainin to the substrate surface decreased nonspecific cell binding as well as led to improved detection limit for bacterial cells such as Salmonella and E. coli.

[edit] Bacterial Resistance

Bacteria uses various resistance strategies to avoid antimicrobial peptide killing.[8] Some microorganisms alter net surface charges. Staphylococcus aureus transports D-alanine from the cytoplasm to the surface teichoic acid to reduce the net negative charge by introducing basic amino groups.[24] S. aureus also modifies its anionic membranes via MprF with L-lysine, increasing the positive net charge.[24] The interaction of antimicrobial peptides with membrane targets can be limited by capsule polysaccharide of Klebsiella pneumoniae.[25] Alterations occur in Lipid A. Salmonella species reduce the fluidity of their outer membrane by increasing hydrophobic interactions between an increased number of Lipid A acyl tails by adding myristate to Lipid A with 2-hydroxymyristate and forming hepta-acylated Lipid A by adding palmitate. The increased hydrophobic moment is though to retard or abolish antimicrobial peptide insertion and pore formation. The residues undergo alteration in membrane proteins. In some Gram-negative bacteria, alteration in the production of outer membrane proteins correlates with resistance to killing by antimicrobial peptides.[26] ATP-binding cassette transporters import antimicrobial peptides and the resistance-nodulation cell-division efflux pump exports antimicrobial peptides.[27] Both transporters have been associated with antimicrobial peptide resistance. Bacteria produce proteolytic enzymes,which may degrade antimicrobial peptides leading to their resistance.[28]

[edit] Examples

Examples of antimicrobal peptides include magainins, alamethicin, pexiganan or MSI-78, and other MSI peptides like MSI-843 and MSI-594, polyphemusin, human antimicrobial peptide, LL-37, defensins and protegrins.

[edit] See also

[edit] References

  1. ^ Template:Moore
  2. ^ a b Yeaman & Yount 2003
  3. ^ Papagianni 2003
  4. ^ Sitaram & Nagaraj 2002
  5. ^ Dürr, Sudheendra & Ramamoorthy 2006
  6. ^ Dhople, Krukemeyer & Ramamoorthy 2006
  7. ^ Hancock & Rozek 2002
  8. ^ a b c Brogden 2005
  9. ^ Amsterdam 1996
  10. ^ Hunter et al. 2002
  11. ^ Hoskin & Ramamoorthy 2008
  12. ^ Mátyus, Kandt & Tieleman 2007
  13. ^ Langham, Ahmad & Kaznessis 2008
  14. ^ Hallock, Lee & Ramamoorthy 2003
  15. ^ Wildman, Lee & Ramamoorthy 2003
  16. ^ a b Matsuzaki 2008
  17. ^ a b Hancock & Sahl 2006
  18. ^ a b Zasloff 2002
  19. ^ a b Matsuzaki et al. 1995
  20. ^ Chou et al. 2008
  21. ^ Tennessen 2005
  22. ^ Lanlan Yu, Lin Guo, Jeak Ling Ding, Bow Ho, Si-Shen Feng, Jonathan Popplewell, Marcus Swann, Thorsten Wohland. Interaction of an artificial antimicrobial peptide with lipid membranes. Biochimica et Biophysica Acta (BBA) - Biomembranes, Volume 1788, Issue 2, February 2009, Pages 333-344, Available online 25 October 2008
  23. ^ Tzong-Hsien Lee, Kristopher Hall, Adam Mechler, Lisandra Martin, Jonathan Popplewell, Gerry Ronan, Marie-Isabel Aguilar Molecular Imaging and Orientational Changes of Antimicrobial Peptides in Membranes American Peptide Society (2007) Peptides for Youth. Eds. Emanuel Escher, William D. Lubell, Susan Del Valle
  24. ^ a b Peschel et al. 1999
  25. ^ Campos et al. 2004
  26. ^ China et al. 1994
  27. ^ Nikaido 1996
  28. ^ Whitelock et al. 1996
  • Amsterdam, D. (1996), "Susceptibility testing of Antimicrobials in liquid media", in Lorian, V., Antibiotics in Laboratory Medicine (Fourth ed.), Baltimore, Md.: Williams and Wilkins, pp. 52–111 
  • Brogden, K.A. (March 2005), "Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria?", Nature Reviews Microbiology 3: 238–250., doi:10.1038/nrmicro1098 
  • Campos, M.A.; Vargas, M.A.; Regueiro, V.; Llompart, C.M.; Alberti, S.; Bengoechea, J.A. (December 2004), Weiser, J.N., ed., "Capsule Polysaccharide Mediates Bacterial Resistance to Antimicrobial Peptides", Infection and Immunity 72 (12): 7107–7114, doi:10.1128/IAI.72.12.7107-7114.2004 
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  • Hallock, K.J.; Lee, D.K.; Ramamoorthy, A. (May 2003), "MSI-78, an analogue of the magainin antimicrobial peptides, disrupts lipid bilayer structure via positive curvature strain", Biophys. J. 84 (5): 3052–3060, doi:10.1016/S0006-3495(03)70031-9, PMID 12719236 
  • Hancock, Robert E.W.; Rozek, A. (2002), "Role of membranes in the activities of antimicrobial cationic peptides.", FEMS Microbiology Letters 206 (2): 143–149, doi:10.1111/j.1574-6968.2002.tb11000.x 
  • Hancock, Robert E.W.; Sahl, Hans-Georg (2006), "Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies", Nature Biotechnology 24: 1551–1557, doi:10.1038/nbt1267 
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  • Hunter, H.N.; Fulton, D.B.; Ganz, T.; Vogel, H.J. (October 2002), "The solution structure of human hepcidin, a peptide hormone with antimicrobial activity that is involved in iron uptake and hereditary hemochromatosis.", J Biol Chem 277 (40): 37597–37603, PMID 12138110 
  • Langham, Allison A.; Ahmad, Abdallah Sayyed; Kaznessis, Yiannis N. (April 2008), "On the Nature of Antimicrobial Activity: A Model for Protegrin-1 Pores", J. Am. Chem. Soc. 130 (13): 4338–4346, PMID 18335931 
  • Matsuzaki, Katsumi (2008), "Control of cell selectivity of antimicrobial peptides", Biochimica et Biophysica Acta – Biomembranes, doi:10.1016/j.bbamem.2008.09.013 
  • Matsuzaki, Katsumi; Ken-ichi, S.; Nobutaka, F.; Koichiro, M. (March 1995), "Molecular Basis for Membrane Selectivity of an Antimicrobial Peptides, Magainin 2", Biochemistry 34 (10): 3423–3429, doi:10.1021/bi00010a034 
  • Mátyus, Edit; Kandt, Christian; Tieleman, D Peter (2007), "Computer simulation of antimicrobial peptides", Curr Med Chem 14 (26): 2789–98, PMID 18045125 
  • Moore, A.J.; Devine,, D.A.; Bibby,, M.C. (1994), "Preliminary experimental anticancer activity of cecropins", Peptide Research 7: 265–269 
  • Nikaido, H. (October 1996), "Multidrug efflux pumps of gram-negative bacteria", Journal of Bacteriology 178 (20): 5853–5859, PMID 8830678 
  • Papagianni, M. (September 2003), "Ribosomally synthesized peptides with antimicrobial properties: biosynthesis, structure, function, and applications", Biotechnol Adv 21 (6): 465–499, PMID 14499150 
  • Peschel, A.; Otto, M.; Jack, R.W.; Kalbacher, H.; Jung, G.; Götz, F. (March 1999), "Inactivation of the dlt operon in Staphylococcus aureus confers sensitivity to defensins, protegrins, and other antimicrobial peptides", Journal of Biological Chemistry 274 (13): 8405–8410, PMID 10085071 
  • Sitaram, N.; Nagaraj, R. (2002), "Host-defense antimicrobial peptides: importance of structure for activity", Curr Pharm Des 8 (9): 727–742, PMID 11945168 
  • Tennessen, Jacob A. (November 2005), "Molecular evolution of animal antimicrobial peptide: widespread moderate positive selection", Journal of Evolutionary Biology 18 (6): 1387–1394, PMID 16313451 
  • Whitelock, J.M.; Murdoch, A.D.; Iozzo, R.V.; Underwood, P.A. (April 1996), "The Degradation of Human Endothelial Cell-derived Perlecan and Release of Bound Basic Fibroblast Growth Factor by Stromelysin, Collagenase, Plasmin, and Heparanases", Journal of Biological Chemistry 271 (17): 10079–10086, PMID 8626565 
  • Wildman, K.A.H.; Lee, D.K.; Ramamoorthy, A. (2003), "Mechanism of Lipid Bilayer Disruption by the Human Antimicrobial Peptide, LL-37", Biochemistry 42 (21): 6545–6558, doi:10.1021/bi0273563 
  • Yeaman, M.R.; Yount, N.Y. (March 2003), "Mechanisms of antimicrobial peptide action and resistance", Pharmacological reviews 55 (1): 27–55, doi:10.1124/pr.55.1.2 
  • Brogden, K.A. (March 2005), "Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria?", Nature Reviews Microbiology 3: 238–250., doi:10.1038/nrmicro1098 
  • Zasloff, Michael (January 2002), "Antimicrobial peptides of multicellular organisms", Nature 415 (6870): 389–395, PMID 11807545 

[edit] External links

v • d • e
Antimicrobial peptides: Granulocyte granule contents
Azurophil granules
Neutrophil specific granules
Eosinophil granules
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