Antimicrobial peptides

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.

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.Fact|date=December 2007 Unlike the majority of conventional antibiotics it appears as though antimicrobial peptides may also have the ability to enhance immunity by functioning as immunomodulators.

tructure

Antimicrobial peptides are short peptides, generally between 12 and 50. 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.ref|papagiannietalref|sitarametalref|durretal 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.ref|dhopleetal Many of these peptides are unstructured in free solution, and fold into their final configuration upon partitioning into biological membranes. The ability to associate with membranes is a definitive feature of antimicrobial peptides ref|hancocketal 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.

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. 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%.ref|nclssamsterdam

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 ref|hunteretal).

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 ref|Hoskinetal, and topical skin infections. Pexiganan has been shown to be useful to treat infection related diabetic foot ulcer.

Models of Antimicrobial Peptides

Computer simulations have recently provided atomistic resolution pictures of how antimicrobial peptides interact with membranes.ref|Tielemanref|Langham. Biophysical studies utilizing solid-state NMR experiments provided atomistic-level resolution explanation of the membrane disruption by antimicrobial peptides.ref|Hallocketalref|Wildmanetal.

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.

Notes and references

# Papagianni, M. 2003. Ribosomally synthesized peptides with antimicrobial properties: biosynthesis, structure, function, and applications. Biotechnol Adv 21:465.
# Sitaram, N., and R. Nagaraj. 2002. Host-defense antimicrobial peptides: importance of structure for activity. Curr Pharm Des 8:727.
#Dürr, U.H.N., Sudheendra, U.S., and Ramamoorthy, A. 2006. LL-37, the only human member of the cathelicidin family of antimicrobial peptides, Biochim. Biophys. Acta 1758: 1408-1425.
#Dhople, V., Krukemeyer, A., and Ramamoorthy, A. 2006. The human beta-defensin-3, an antibacterial peptide with multiple biological functions, BBA Biomembranes 1758: 1499-1512.
# Hancock, R. E. W., and A. Rozek. 2002. Role of membranes in the activities of antimicrobial cationic peptides. FEMS Microbiol Lett 206:143.
# National Committee of Laboratory Safety and Standards (NCLSS) as published in Amsterdam, D. 1996. Susceptibility testing of Antimicrobials in liquid media. In "Antibiotics in Laboratory Medicine", Lorian, V., ed. Fourth Edition, pp.52-111. Williams and Wilkins, Baltimore
# Hunter, H. N., D. B. Fulton, T. Ganz, and H. J. Vogel. 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 277:37597.
# Hoskin, D.W. and Ramamoorthy, A. Studies on anticancer activities of antimicrobial peptides. (2008). BBA Biomembranes 1778: 357-375.
# Edit Mátyus, Christian Kandt, D Peter Tieleman, Curr Med Chem. 2007 ;14 (26):2789-98 18045125 Computer simulation of antimicrobial peptides.
# Allison A. Langham, Abdallah Sayyed Ahmad, and Yiannis N. Kaznessis, J. Am. Chem. Soc., 130 (13), 4338 -4346, 2008. On the Nature of Antimicrobial Activity: A Model for Protegrin-1 Pores.
# Hallock, K.J., Lee, D.K., and Ramamoorthy, A. (2003). MSI-78, an analogue of the magainin antimicrobial peptides, disrupts lipid bilayer structure via positive curvature strain, Biophys. J. 84: 3052.
# Wildman, K.A.H., Lee, D.K., and Ramamoorthy, A. (2003) Mechanism of lipid bilayer disruption by the human antimicrobial peptide, LL-37, Biochemistry 42: 6545.

External links

* [http://www.scq.ubc.ca/?p=405 A good basic overview of cationic peptides] at scq.ubc.ca
* [http://www.ejbiotechnology.info/content/vol6/issue3/full/1/index.html Review with helpful links] at ejbiotechnology.info
* [http://aps.unmc.edu/AP/main.php Antimicrobial Peptide Database] at unmc.edu
* - Calculated spatial positions of peptides in the lipid bilayer
*

ee also

* Peripheral membrane proteins

* Cathelicidin