ISSN 1214-0287 (on-line), ISSN 1214-021X (printed)
J Appl Biomed
Volume 8 (2010), No 3, p 159-167
DOI 10.2478/v10136-009-0019-3

Membrane-active peptides as anti-infectious agents

Luis Rivas, Juan Roman Luque-Ortega, Maria Fernandez-Reyes, David Andreu

Address: Luis Rivas, Centro de Investigaciones Biologicas - CSIC, Ramiro de Maeztu 9, E-28040 Madrid, Spain
luis.rivas@cib.csic.es

Received 15th March 2010.
Revised 23rd April 2010.
Published online 12th May 2010.

Full text article (pdf)
Full text article (html)
Abstract in xml format

SUMMARY
The lipid components of pathogen cell membranes have been considered as a poor pharmacological target, due to their universal distribution and apparent homogeneity throughout living organisms. Among the rare exceptions to this view one could mention polyene antibiotics such as amphotericin, or peptide antibiotics such as the polymyxins and the gramicidins. In the last two decades, however, the above notion has been challenged by two main lines of discovery; first, natural antimicrobial peptides (AMPs) that kill pathogens by interaction with phospholipids and membrane permeabilization, and secondly, cell-penetrating peptides (CPPs), capable of introducing into cells a variety of cargoes in the absence of specific receptors, again by interaction at some point with membrane phospholipids. For both AMPs and CPPs, the pharmacological proof-of-concept has been successfully demonstrated, and promising applications as nanobiotechnological tools have been envisaged though not hitherto materialized in clinical settings. In this review we briefly examine the pros and cons of these two classes of therapeutic agents, as well as strategies aimed at rationalizing and expanding their potentiality.

KEY WORDS
membrane; cell-penetrating peptide; antimicrobial peptide; antibiotic resistance; infectious disease

REFERENCES
Alves ID, Jiao CY, Aubry S, Aussedat B, Burlina F, Chassaing G, Sagan S: Cell biology meets biophysics to unveil the different mechanisms of penetratin internalization in cells. Biochim Biophys Acta 2010, doi:10.1016/j.bbamem.2010.02.009.

Brogden KA, Ackermann M, Huttner KM: Detection of anionic antimicrobial peptides in ovine bronchoalveolar lavage fluid and respiratory epithelium. Infect Immun 66:5948-5954, 1998.

Carretero M, Del Rio M, Garcia M, Escamez MJ, Mirones I, Rivas L, Balague C, Jorcano JL, Larcher F: A cutaneous gene therapy approach to treat infection through keratinocyte-targeted overexpression of antimicrobial peptides. FASEB J 18:1931-1933, 2004.

Christensen B, Fink J, Merrifield RB, Mauzerall D: Channel-forming properties of cecropins and related model compounds incorporated into planar lipid membranes. Proc Nat Acad Sci USA 85:5072-5076, 1988.

Dawson RM, Liu CQ: Properties and applications of antimicrobial peptides in biodefense against biological warfare threat agents. Crit Rev Microbiol 34:89-107, 2008.

Hopkins KL, Davies RH, Threlfall EJ: Mechanisms of quinolone resistance in Escherichia coli and Salmonella: recent developments. Int J Antimicrob Agents 25:358-373, 2005.

Hornef MW, Putsep K, Karlsson J, Refai E, Andersson M: Increased diversity of intestinal antimicrobial peptides by covalent dimer formation. Nature Immunol 5:836-843, 2004.

Jerala R, Porro M: Endotoxin neutralizing peptides. Curr Top Med Chem 4:1173-1184, 2004.

Koczan G, Ghose AC, Mookerjee A, Hudecz F: Methotrexate conjugate with branched polypeptide influences Leishmania donovani infection in vitro and in experimental animals. Bioconjug Chem 13:518-524, 2002.

Lehrer RI, Barton A, Daher KA, Harwig SS, Ganz T, Selsted ME: Interaction of human defensins with Escherichia coli. Mechanism of bactericidal activity. J Clin Invest 84:553-561, 1989.

Lemaitre B, Hoffmann J: The host defense of Drosophila melanogaster. Annu Rev Immunol 25:697-743, 2007.

Lupetti A, Welling MM, Pauwels EK, Nibbering PH: Radiolabelled antimicrobial peptides for infection detection. Lancet Infect Dis 3:223-229, 2003.

Luque-Ortega JR, van't Hof W, Veerman EC, Saugar JM, Rivas L: Human antimicrobial peptide histatin 5 is a cell-penetrating peptide targeting mitochondrial ATP synthesis in Leishmania. FASEB J 22:1817-1828, 2008.

Marcos JF, Munoz A, Perez-Paya E, Misra S, Lopez-Garcia B: Identification and rational design of novel antimicrobial peptides for plant protection. Annu Rev Phytopathol 46:273-301, 2008.

Matsuzaki K: Control of cell selectivity of antimicrobial peptides. Biochim Biophys Acta 1788:1687-1692, 2009.

Melo MN, Ferre R, Castanho MA: Antimicrobial peptides: linking partition, activity and high membrane-bound concentrations. Nat Rev Microbiol 7:245-250, 2009.

Metz-Boutigue MH, Shooshtarizadeh P, Prevost G, Haikel Y, Chich JF: Antimicrobial peptides present in mammalian skin and gut are multifunctional defence molecules. Curr Pharm Des 16:1024-1039, 2009.

Mitev GM, Mellbye BL, Iversen PL, Geller BL: Inhibition of intracellular growth of Salmonella enterica serovar Typhimurium in tissue culture by antisense peptide-phosphorodiamidate morpholino oligomer. Antimicrob Agents Chemother 53:3700-3704, 2009.

Mogi T, Kita K: Gramicidin S and polymyxins: the revival of cationic cyclic peptide antibiotics. Cell Mol Life Sci 66:3821-3826, 2009.

Niyonsaba F, Nagaoka I, Ogawa H, Okumura K: Multifunctional antimicrobial proteins and peptides: natural activators of immune systems. Curr Pharm Des 15:2393-2413, 2009.

Otte JM, Zdebik AE, Brand S, Chromik AM, Strauss S, Schmitz F, Steinstraesser L, Schmidt WE: Effects of the cathelicidin LL-37 on intestinal epithelial barrier integrity. Regul Pept 156:104-117, 2009.

Otto M: Bacterial evasion of antimicrobial peptides by biofilm formation. Curr Top Microbiol Immunol 306:251-258, 2006.

Otto M: Bacterial sensing of antimicrobial peptides. Contrib Microbiol 16:136-149, 2009.

Otvos L, Jr.: Antibacterial peptides and proteins with multiple cellular targets. J Pept Sci 11:697-706, 2005.

Peschel A: How do bacteria resist human antimicrobial peptides? Trends Microbiol 10:179-186, 2002.

Powers JP, Tan A, Ramamoorthy A, Hancock REW: Solution structure and interaction of the antimicrobial polyphemusins with lipid membranes. Biochemistry 44:15504-15513, 2005.

Rao KS, Ghorpade A, Labhasetwar V: Targeting anti-HIV drugs to the CNS. Expert Opin Drug Deliv 6:771-784, 2009.

Rodriguez-Hernandez MJ, Saugar JM, Docobo-Perez F, de la Torre BG, Pachon-Ibanez ME, Garcia-Curiel A, Fernandez-Cuenca F, Andreu D, Rivas L, Pachon J: Studies on the antimicrobial activity of cecropin A-melittin hybrid peptides in colistin-resistant clinical isolates of Acinetobacter baumannii. J Antimicrob Chemother 58:95-100, 2006.

Rosenfeld Y, Shai Y: Lipopolysaccharide (Endotoxin)-host defense antibacterial peptides interactions: role in bacterial resistance and prevention of sepsis. Biochim Biophys Acta 1758:1513-1522, 2006.

Santra S, Yang H, Stanley JT, Holloway PH, Moudgil BM, Walter G, Mericle RA: Rapid and effective labeling of brain tissue using TAT-conjugated CdS:Mn/ZnS quantum dots. Chem Commun (Camb) 25:3144-3146, 2005.

Schittek B, Paulmann M, Senyurek I, Steffen H: The role of antimicrobial peptides in human skin and in skin infectious diseases. Infect Disord Drug Targets 8:135-143, 2008.

Selsted ME: theta-defensins: cyclic antimicrobial peptides produced by binary ligation of truncated alpha-defensins. Curr Protein Pept Sci 5:365-371, 2004.

Steinstraesser L, Kraneburg UM, Hirsch T, Kesting M, Steinau HU, Jacobsen F, Al-Benna S: Host defense peptides as effector molecules of the innate immune response: a sledgehammer for drug resistance? Int J Mol Sci 10:3951-3970, 2009.

Sun X, Salih E, Oppenheim FG, Helmerhorst EJ: Kinetics of histatin proteolysis in whole saliva and the effect on bioactive domains with metal-binding, antifungal, and wound-healing properties. FASEB J 23:2691-2701, 2009.

Torchilin VP: Cell penetrating peptide-modified pharmaceutical nanocarriers for intracellular drug and gene delivery. Biopolymers 90:604-610, 2008.

Vives E, Schmidt J, Pelegrin A: Cell-penetrating and cell-targeting peptides in drug delivery. Biochim Biophys Acta 1786:126-138, 2008.

Wade D, Boman A, Wahlin B, Drain CM, Andreu D, Boman HG, Merrifield RB: All-D amino acid-containing channel-forming antibiotic peptides. Proc Nat Acad Sci USA 87:4761-4765, 1990.

Watkins CL, Brennan P, Fegan C, Takayama K, Nakase I, Futaki S, Jones AT: Cellular uptake, distribution and cytotoxicity of the hydrophobic cell penetrating peptide sequence PFVYLI linked to the proapoptotic domain peptide PAD. J Control Release 140:237-244, 2009.

Wu Z, Hoover DM, Yang D, Boulegue C, Santamaria F, Oppenheim JJ, Lubkowski J, Lu W: Engineering disulfide bridges to dissect antimicrobial and chemotactic activities of human beta-defensin 3. Proc Nat Acad Sci USA 100:8880-8885, 2003.

Yang D, de la Rosa G, Tewary P, Oppenheim JJ: Alarmins link neutrophils and dendritic cells. Trends Immunol 30:531-537, 2009.

Zasloff M: Antimicrobial RNases of human skin. J Invest Dermatol 129:2091-2093, 2009.

Zhang L, Falla TJ: Host defense peptides for use as potential therapeutics. Curr Opin Investig Drugs 10:164-171, 2009.
CITED

Prabhu S, Dennison SR, Lea B, Snape TJ, Nicholl ID, Radecka I, Harris F. Anionic Antimicrobial and Anticancer Peptides from Plants. Crit Rev Plant Sci. 32: 303-320, 2013.

Li JG, Liu SP, Lakshminarayanan R, Bai Y, Pervushin K, Verma C, Beuerman RW. Molecular simulations suggest how a branched antimicrobial peptide perturbs a bacterial membrane and enhances permeability. Biochim Biophys Acta Rev Biomembr. 1828: 1112-1121, 2013.

Zetterberg MM, Reijmar K, Pranting M, Engstrom A, Andersson DI, Edwards K. PEG-stabilized lipid disks as carriers for amphiphilic antimicrobial peptides. J Controlled Release. 156: 323-328, 2011.

Torres O, Bong D. Determinants of Membrane Activity from Mutational Analysis of the HIV Fusion Peptide. Biochemistry. 50: 5195-5207, 2011.

Berger J. The age of biomedicine: current trends in traditional subjects. J Appl Biomed. 9: 57-61, 2011.

Seil M, Nagant C, Dehaye JP, Vandenbranden M, Lensink MF. Spotlight on human LL-37, an immunomodulatory peptide with promising cell-penetrating properties. Pharmaceuticals. 3: 3435-3460, 2010.

BACK