The Development of Antimicrobial Peptides as New Antibacterial Drugs

Current Protein and Peptide Science

Volumn 14, Issue 8, 2013, Pages 641-649

  Roscia, Giulia ^a   Falciani, Chiara ^a   Bracci, Luisa ^a,b   Pini, Alessandro ^a,b  

^a UNIVERSITY OF SIENA   (Italy)

^b UNIVERSITY HOSPITAL OF SIENA   (Italy)

Author keywords

Antibiotic resistance; Antimicrobial peptides; Bacterial pathogens; Clinical development; New antibacterials

Indexed keywords

ARENICIN 3; BACITRACIN; CATHELICIDIN ANTIMICROBIAL PEPTIDE LL 37; COLISTIMETHATE; COLISTIN; DAPTOMYCIN; DPK 060; GRAMICIDIN; HLF 1 11; LTX 109; NOVAMYCIN; NOVEXATIN; OMIGANAN; OPEBACAN; PLACEBO; PLX 150; POL 7080; POLYMYXIN B; POLYPEPTIDE ANTIBIOTIC AGENT; RIFAMPICIN; UNCLASSIFIED DRUG; VANCOMYCIN;

ACINETOBACTER INFECTION; ANTIMICROBIAL ACTIVITY; ARTICLE; ATOPIC DERMATITIS; BACTERIAL INFECTION; CONTINUOUS INFUSION; CYSTIC FIBROSIS; DRUG SAFETY; EAR INFECTION; EXTERNAL OTITIS; EYE INFECTION; HUMAN; LEG ULCER; MENINGOCOCCEMIA; MOLECULAR DYNAMICS; MULTICENTER STUDY (TOPIC); MYCOSIS; NONHUMAN; NOSE INFECTION; ONYCHOMYCOSIS; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PSEUDOMONAS INFECTION; SKIN INFECTION; STAPHYLOCOCCUS INFECTION;

ANIMALS; ANTI-BACTERIAL AGENTS; BACTERIA; BACTERIAL INFECTIONS; HUMANS; PEPTIDES;

EID: 84891757491     PISSN: 13892037     EISSN: 18755550     Source Type: Journal    
DOI: 10.2174/138920371408131227155308     Document Type: Article

References (117)

1. Chakravortty, D. Report from the Global Health Meets Infection Biology LSS2012 Program: Infectious diseases and their management, a light at the end of tunnel? August 2012. Virulence, 2013, 17, 4.
2. French, G.L. The continuing crisis in antibiotic resistance. Int. J. Antimicrob. Agents, 2010, 36 (Suppl 3), S3-S7.
3. Avner, B.S.; Fialho, A.M.; Chakrabarty, A.M. Overcoming drug resistance in multi-drug resistant cancers and microorganisms: a conceptual framework. Bioengineered, 2012, 3, 262-270.
4. Bourlioux, P. Which alternatives are at our disposal in the antiinfectious therapeutics face to multi-drug resistant bacteria? Ann. Pharm. Fr., 2013, 71, 150-158.
5. Schmidt, F.R. The challenge of multidrug resistance: actual strategies in the development of novel antibacterials. Appl Microbiol. Biotechnol., 2004, 63, 335-343.
6. Spellberg, B.; Guidos, R.; Gilbert, D.; Bradley, J.; Boucher, H.W.; Scheld, W.M.; Bartlett, J.G.; Edwards, J. Jr.; Infectious Diseases Society of America. The epidemic of antibiotic resistant infections: a call to action for the medical community from the Infectious Diseases Society of America. Clin. Infect. Dis., 2008, 46, 155-164.
7. Vonberg, R.P.; Wolter, A.; Ziesing, S.; Gastmeier, P. Surveillance of cystic fibrosis patients with multi-drug resistant Gram-negative rods. Int. J. Hyg. Environ Health, 2006, 209, 333-336.
8. Daneshpour, N.; Collighan, R.; Perrie, Y.; Lambert, P.; Rathbone, D.; Lowry, D.; Griffin, M. Indwelling catheters and medical implants with FXIIIa inhibitors: A novel approach to the treatment of catheter and medical device-related infections. Eur. J. Pharm. Biopharm., 2013, 83, 106-113.
9. Ayraud-Thévenot, S.; Huart, C.; Mimoz, O.; Taouqi, M.; Laland, C.; Bousseau, A.; Castel, O. Control of multi-drug-resistant Acinetobacter baumannii outbreaks in an intensive care unit: feasibility and economic impact of rapid unit closure. O.J. Hosp. Infect., 2012, 82, 290-292.
10. López-Cerero, L.; Fernández-Cuenca, F.; Pascual, A. The Microbiolgy laboratory in nosocomial infection surveillance and control. Enferm. Infecc. Microbiol. Clin., 2013, 31, 44-51.
11. Tomono, K. The managements of nosocomial outbreaks of multidrug resistant bacteria. Nihon. Rinsho., 2012, 70, 320-323.
12. Macfarlane, J. BTS guidelines for the management of community acquired pneumonia in adults. Thorax, 2001, 56 (IV), 1-64.
13. Brown, K.L.; Hancock, R.E. Cationic host defense (antimicrobial) peptides. Curr. Opin. Immunol., 2006, 18, 24-30.
14. Zasloff, M. Antimicrobial peptides of multicellular organisms. Nature, 2002, 415, 389-395.
15. Easton, D.M.; Nijnik, A.; Mayer, M.L.; Hancock, R.E.W. Potential of immunomodulatory host defense peptides as novel antiinfectives. Trends Biotechnol., 2009, 27, 582-590.
16. Choi, K.Y.; Chow, L.N.; Mookherjee, N. Cationic host defence peptides: multifaceted role in immune modulation and inflammation. J. Innate Immun., 2012, 4, 361-370.
17. Hamill, P.; Brown, K.; Jenssen, H.; Hancock, R.E. Novel antiinfectives: is host defence the answer? Curr. Opin. Biotechnol., 2008, 19, 628-636.
18. Hancock, R.E.W.; Sahl, H.G. Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat. Biotechnol., 2006, 24, 1551-1557.
19. Marr, A.K.; Gooderham, W.J.; Hancock, R.E. Antibacterial peptides for therapeutic use: Obstacles and realistic outlook. Curr. Opin. Pharmacol., 2006, 6, 468-472.
20. Wiesner, J.; Vilcinskas, A. Antimicrobial peptides: the ancient arm of the human immune system. Virulence, 2010, 1, 440-464.
21. Hale, J.D.F.; Hancock, R.E.W. Alternative mechanisms of action of cationic antimicrobial peptides on bacteria. Expert Rev. Anti Infect. Ther., 2007, 5, 951-959.
22. Shu, M.; Jiang, Y.; Yang, L.; Wu, Y.; Mei, H.; Li, Z. Application of 'HESH' descriptors for the structure-activity relationships of antimicrobial peptides. Protein Pept. Lett., 2009, 16, 143-149.
23. Pate, M.; Blazyk, J. Methods for assessing the structure and function of cationic antimicrobial peptides. Methods Mol. Med., 2008, 142, 155-173.
24. Huang, Y.; Huang, J.; Chen, Y. Alpha-helical cationic antimicrobial peptides: relationships of structure and function. Protein Cell., 2010, 1, 143-152.
25. Oren, Z.; Shai, Y. Mode of action of linear amphipathic alphahelical antimicrobial peptides. Biopolymers, 1998, 47, 451-463.
26. Ehrenstein, G.; Lecar, H. Electrically gated ionic channels in lipid bilayers. Q. Rev. Biophys. 1977, 10, 1-34.
27. Wu, M.H.; Maier, E.; Benz, R.; Hancock, R.E.W. Mechanism of interaction of different classes of cationic antimicrobial peptides with planar bilayers and with the cytoplasmic membrane of Escherichia coli. Biochemistry (NY), 1999, 38, 7235-7242.
28. Chongsiriwatana, N.P.; Barron, A.E. Comparing bacterial membrane interactions of antimicrobial peptides and their mimics. Methods Mol. Biol., 2010, 618, 171-182.
29. Yang, L.; Harroun, T.A.; Weiss, T.M.; Ding, L.; Huang, H.W. Barrel-stave model or toroidal model? A case study on melittin pores. Biophys. J., 2001, 81, 1475-1485.
30. Shai, Y. Mode of action of membrane active antimicrobial peptides. Biopolymers, 2002, 66, 236-248.
31. Bagheri, M.; Beyermann, M.; Dathe, M. Mode of action of cationic antimicrobial peptides defines the tethering position and the efficacy of biocidal surfaces. Bioconjug. Chem., 2012, 1823, 66-74.
32. Yount, N.Y.; Yeaman, M.R. Peptide antimicrobials: cell wall as a bacterial target. Ann. N.Y. Acad. Sci., 2013, 1277, 127-138.
33. van't Hof, W.; Veerman, E.C.; Helmerhorst, E.J.; Amerongen, A.V. Antimicrobial peptides: Properties and applicability. Biol. Chem., 2001, 382, 597-619.
34. Hassan, M.; Kjos, M.; Nes, I.F.; Diep, D.B.; Lotfipour, F. Natural antimicrobial peptides from bacteria: characteristics and potential applications to fight against antibiotic resistance. J. Appl. Microbiol., 2012, 113, 723-736.
35. Anaya-López, J.L.; López-Meza, J.E.; Ochoa-Zarzosa, A. Bacterial resistance to cationic antimicrobial peptides. Crit. Rev. Microbiol., 2013, 39, 180-195.
36. Gruenheid, S.; Le Moual, H. Resistance to antimicrobial peptides in Gram-negative bacteria. FEMS Microbiol. Lett., 2012, 330, 81-89.
37. Koprivnjak, T.; Peschel, A. Bacterial resistance mechanisms against host defense peptides. Cell Mol. Life Sci., 2011, 68, 2243-2254.
38. Kraus, D.; Peschel, A. Molecular mechanisms of bacterial resistance to antimicrobial peptides. Curr. Top. Microbiol. Immunol., 2006, 306, 231-250.
39. Campos, M.A.; Vargas, M.A.; Regueiro, V.; Llompart, C.M.; Albertí, S.; Bengoechea, J.A. Capsule polysaccharide mediates bacterial resistance to antimicrobial peptides. Infect. Immun., 2004, 72, 7107-7114.
40. Devine, D.A.; Hancock, R.E. Cationic peptides: distribution and mechanisms of resistance. Curr. Pharm. Des., 2002, 8, 703-714.
41. Gunn, J.S. Bacterial modification of LPS and resistance to antimicrobial peptides. J. Endotoxin Res., 2001, 7, 57-62.
42. Wright, G.D. Bacterial resistance to antibiotics: Enzymatic degradation and modification. Adv. Drug Deliv. Rev., 2005, 57, 1451-1470.
43. Teixeira, V.; Feio, M.J.; Bastos, M. Role of lipids in the interaction of antimicrobial peptides with membranes. Prog. Lipid Res., 2012, 51, 149-177.
44. Svenson, J.; Stensen, W.; Brandsdal, B.; Haug, B.E.; Monrad, J.; Svendsen, J.S. Antimicrobial peptides with stability toward tryptic degradation. Biochemistry (NY), 2008, 47, 3777-3788.
45. Falciani, C.; Lozzi, L.; Pini, A.; Corti, F.; Fabbrini, M.; Bernini, A.; Lelli, B.; Niccolai, N.; Bracci, L. Molecular basis of branched peptides resistance to enzyme proteolysis. Chem. Biol. Drug Des., 2007, 69, 216-221.
46. Galati, R.; Verdina, A.; Falasca, G.; Chersi, A. Increased resistance of peptides to serum proteases by modification of their amino groups. Z. Naturforsch C., 2003, 58, 558-561.
47. Papo, N.; Shai, Y. Effect of drastic sequence alteration and Damino acid incorporation on the membrane binding behavior of lytic peptides. Biochemistry (NY), 2004, 43, 6393-6403.
48. Shai, Y.; Oren, Z. From "carpet" mechanism to de novo designed diastereomeric cell-selective antimicrobial peptides. Peptides, 2001, 22, 1629-1641.
49. Pini, A.; Falciani, C.; Bracci, L. Branched peptides as therapeutics. Curr. Protein Pept. Sci., 2009, 10, 194-195.
50. U. S Food and Drug Administration. FDA approved drug products. http: //www. accessdata. fda. gov/scripts/cder/drugsatfda/index. cfm?f useaction=Search. DrugDetails (Accessed May, 25 2013).
51. Karala, A.R.; Ruddock L.W. Bacitracin is not a specific inhibitor of protein disulfide isomerase. FEBS J., 2010, 277, 2454-2462.
52. Vaara, M.; Novel derivatives of polymyxins. J. Antimicrob. Chemother., 2013, 68, 1213-1219.
53. Moskowitz, S.M.; Brannon, M.K.; Dasgupta, N.; Pier, M.; Sgambati, N.; Miller, A.K.; Selgrade, S.E.; Miller, S.I.; Denton, M.; Conway, S.P.; Johansen, H.K.; Høiby, N. PmrB mutations promote polymyxin resistance of Pseudomonas aeruginosa isolated from colistin-treated cystic fibrosis patients. Antimicrob. Agents Chemother., 2012, 56, 1019-1030.
54. Neonakis, I.K.; Samonis, G.; Messaritakis, H.; Baritaki, S.; Georgiladakis, A.; Maraki, S.; Spandidos, D.A. Resistance status and evolution trends of Klebsiella pneumoniae isolates in a university hospital in Greece: ineffectiveness of carbapenems and increasing resistance to colistin. Chemotherapy, 2010, 56, 448-452.
55. Lee G.C.; Burgess D.S. Polymyxins and Doripenem Combination Against KPC-Producing Klebsiella pneumonia. J. Clin. Med. Res., 2013, 5, 97-100.
56. U. S Food and Drug Administration. FDA approved drug products. http: //www. accessdata. fda. gov/scripts/cder/drugsatfda/index. cfm?f useaction=Search. DrugDetails (Accessed May 26, 2013).
57. Schuster, A.; Haliburn, C.; Döring, G.; Goldman, M.H. Safety, efficacy and convenience of colistimethate sodium dry powder for inhalation (Colobreathe DPI) in patients with cystic fibrosis: a randomised study. Thorax, 2013, 68, 344-350.
58. Healan, A.M.; Gray, W.; Fuchs, E.J.; Griffiss, J.M.; Salata, R.A.; Blumer, J. Stability of colistimethate sodium in aqueous solution. Antimicrob. Agents Chemother., 2012, 56, 6432-6433.
59. de Boer, A.H.; Le Brun, P.P.; van der Woude, H.G.; Hagedoorn, P.; Heijerman, H.G.; Frijlink, H.W. Dry powder inhalation of antibiotics in cystic fibrosis therapy, part 1: development of a powder formulation with colistin sulfate for a special test inhaler with an air classifier as de-agglomeration principle. Eur. J. Pharm. Biopharm., 2002, 54, 17-24.
60. Spapen H.; Jacobs, R.; Van Gorp, V.; Troubleyn, J.; Honoré P.M. Renal and neurological side effects of colistin in critically ill patients. Annals of Intensive Care, 2011, 1, 14.
61. ClinicalTrials. gov. A service of the U. S National Institutes of Health. http: //www. clinicaltrials. gov/ct2/show/NCT01577862?term=colisti n+rifampicin&rank=1 (Accesed May 27, 2013).
62. Domingues, M.M.; Inácio, R.G.; Raimundo, J.M.; Martins, M.; Castanho, M.A.; Santos, N.C. Biophysical characterization of polymyxin B interaction with LPS aggregates and membrane model systems. Biopolymers, 2012, 98, 338-344.
63. Biswas, S.; Brunel, J.M.; Dubus, J.C.; Reynaud-Gaubert, M.; Rolain J.M. Colistin: an update on the antibiotic of the 21st century. Expert Rev. Anti Infect. Ther., 2012, 10, 917-934.
64. U. S Food and Drug Administration. FDA approved drug products. http: //www. accessdata. fda. gov/scripts/cder/drugsatfda/index. cfm?f useaction=Search. DrugDetails (Accessed May 28, 2013).
65. Alder, J.D. Daptomycin, a new drug class for the treatment of Gram-positive infections. Drugs Today, 2005, 41 (2), 81-90.
66. Cubist Pharmaceuticals. Products and pipeline. http: //www. cubist. com/products/cubicin (Accessed May 31, 2013).
67. Palma, D.M.; Giordano, S.; Neville Cracchiolo, A.; Zangara, V.; Coffaro, G.; Tetamo, R. Daptomycin in the treatment of invasive Gram-positive bacterial infections in children: personal experience. Minerva Pediatr., 2013, 65, 173-178.
68. Dortet, L.; Anguel, N.; Fortineau, N.; Richard, C.; Nordmann, P. In vivo acquired daptomycin resistance during treatment of methicillin-resistant Staphylococcus aureus endocarditis. Int. J. Infect. Dis., 2013, 17 (11), e1076-e1077.
69. Kullar, R.; Davis, S.L.; Kaye, K.S.; Levine, D.P.; Pogue, J.M.; Rybak, M.J. Implementation of an antimicrobial stewardship pathway with daptomycin for optimal treatment of methicillinresistant Staphylococcus aureus bacteremia. Pharmacotherapy, 2013, 33, 3-10.
70. Mohr, J.F.; Murray, B.E. Point: Vancomycin is not obsolete for the treatment of infection caused by methicillin-resistant Staphylococcus aureus. Clin. Infect. Dis., 2007, 44, 1536-1542.
71. Griffith, R.S. Introduction to vancomycin. Rev. Infect. Dis., 1981, 3, S200-S204.
72. Moellering, R.C. Jr. Vancomycin: a 50-year reassessment. Clin. Infect. Dis., 2006, 42 Suppl 1, S3-S4.
73. Mogi, T.; Kita, K. Gramicidin S and polymyxins: the revival of cationic cyclic peptide antibiotics. Cell Mol. Life Sci., 2009, 66, 3821-3826.
74. Carvalho, C.A.; Olivares-Ortega, C.; Soto-Arriaza, M.A.; Carmona-Ribeiro, A.M. Interaction of gramicidin with DPPC/DODAB bilayer fragments. Biochim. Biophys. Acta., 2012, 1818, 3064-3071.
75. Xellia Pharmaceuticals. Products. http: //www. xellia. com/files/files/ Products/APIs/Gramicidin. pdf (Accessed May 31, 2013).
76. Srinivas, N.; Jetter, P.; Ueberbacher, B.J.; Werneburg, M.; Zerbe, K.; Steinmann, J.; Van der Meijden, B.; Bernardini, F.; Lederer, A.; Dias, R.L.A.; Misson, P.E.; Henze, H.; Zumbrunn, J.; Gombert, F.O.; Obrecht, D.; Hunziker, P.; Schauer, S.; Ziegler, U.; Käch, A.; Eberl, L.; Riedel, K.; DeMarco, S.J.; Robinson J.A. Peptidomimetic Antibiotics Target Outer-Membrane Biogenesis in Pseudomonas aeruginosa. Science, 2010, 327, 1010-1013.
77. Polyphor. Products. http: //www. polyphor. com/pol7080. html (Accessed May 31, 2013).
78. Brouwer, C.P.; Rahman, M.; Welling, M.M. Discovery and development of a synthetic peptide derived from lactoferrin for clinical use. Peptides, 2011, 32, 1953-1963.
79. Dijkshoorn, L.; Brouwer, C.P.; Bogaards, S.J.; Nemec, A.; van den Broek, P.J.; Nibbering, P.H. The synthetic N-terminal peptide of human lactoferrin, hLF (1-11), is highly effective against experimental infection caused by multidrug-resistant Acinetobacter baumannii. Antimicrob. Agents Chemother., 2004, 48, 4919-4921.
80. Lupetti, A.; Paulusma-Annema, A.; Welling, M.M.; Senesi, S.; van Dissel, J.T.; Nibbering, P.H. Candidacidal activities of human lactoferrin peptides derived from the N terminus. Antimicrob. Agents Chemother., 2000, 44, 3257-3263.
81. ClinicalTrials. gov. A service of the U. S National Institutes of Health. http: //www. clinicaltrials. gov/ct2/show/NCT00509938?term=hLF1-11&rank=2 (Accessed May 29, 2013).
82. ClinicalTrials. gov. A service of the U. S National Institutes of Health. http: //www. clinicaltrials. gov/ct2/show/NCT00509834?term=hLF1-11&rank=1 (Accessed May 29, 2013).
83. NovaBiotics Ltd. Novamycin. http: //www. novabiotics. co. uk/ NovamycinAugust% 202012. pdf (Accessed May 31, 2013).
84. TM. Novexatin. http: //www. evaluategroup. com/ Universal/ View. aspx?type=Entity&entityType=Product&lType=modData &id=32164&componentID=1002 (Accessed May 31, 2013).
85. NovaBiotics Ltd. Novexatin. http: //www. novabiotics. co. uk/ novexatin/Novabiotics%20Novexatin%20for%20Printer. pdf (Accessed May 31, 2013).
86. Saravolatz, L. D; Pawlak, J.; Johnson, L.; Bonilla, H.; Saravolatz, L.D. 2nd; Fakih, M.G.; Fugelli, A.; Olsen, W.M. In vitro activities of LTX-109, a synthetic antimicrobial peptide, against methicillin-resistant, vancomycin-intermediate, vancomycin-resistant, daptomycin-nonsusceptible, and linezolid-nonsusceptible Staphylo coccus aureus. Antimicrob. Agents Chemother., 2012, 56, 4478-4482.
87. Isaksson, J.; Brandsdal, B.O.; Engqvist, M.; Flaten, G.E.; Svendsen, J.S.; Stensen, W. A synthetic antimicrobial peptidomimetic (LTX 109): stereochemical impact on membrane disruption. J. Med. Chem., 2011, 25 (54), 5786-5795.
88. ClinicalTrials. gov. A service of the U. S National Institutes of Health. http: //www. clinicaltrials. gov/ct2/show/NCT01803035?term=LTX-109&rank=1 (Accessed May 30, 2013).
89. ClinicalTrials. gov. A service of the U. S National Institutes of Health. http: //www. clinicaltrials. gov/ct2/show/NCT01447017?term=DPK %E2%80%90060&rank=1 (Accessed May 30, 2013).
90. ClinicalTrials. gov. A service of the U. S National Institutes of Health. http: //www. clinicaltrials. gov/ct2/show/NCT01522391?term=DPK %E2%80%90060&rank=2 (Accessed May 30, 2013).
91. Zanetti, M. The role of cathelicidins in the innate host defenses of mammals. Curr. Issues Mol. Biol., 2005, 7, 179-196.
92. Zanetti, M.; Gennaro, R.; Scocchi, M.; Skerlavaj, B. Structure and biology of Cathelicidins. Adv. Exp. Med. Biol., 2000, 479, 203-218.
93. Durr, U.H.; Sudheendra, U.S.; Ramamoorthy, A. LL-37, the only human member of the cathelicidin family of antimicrobial peptides. Biochim. Biophys. Acta., 2006, 1758, 1408-1425.
94. Lai, Y.; Adhikarakunnathu, S.; Bhardwaj, K.; Ranjith-Kumar, C.T.; Wen, Y.; Jordan, J.L.; Wu, L.H.; Dragnea, B.; San Mateo, L.; Kao, C.C. LL37 and cationic peptides enhance TLR3 signaling by viral double-stranded RNAs. PLoS One, 2011, 6, 26632.
95. Business Wire. News. Pergamum announces last visit of last patient in a Phase I/II trial of a potential new treatment for hard-toheal wounds. http: //www. businesswire. com/news/home/20130418006830/en/Kar olinska-Development-AB-publ-Pergamum-announces-visit (Accessed May 31, 2013).
96. Sader, H.S.; Fedler, K.A.; Rennie, R.P.; Stevens, S.; Jones R.N. Omiganan Pentahydrochloride (MBI 226), a Topical 12-Amino-Acid Cationic Peptide: Spectrum of Antimicrobial Activity and Measurements of Bactericidal Activity. Antimicrob. Agents Chemotherap., 2004, 48, 3112-3118.
97. ClinicalTrials. gov. A service of the U. S National Institutes of Health. http: //www. clinicaltrials. gov/ct2/show/NCT01784133?term=cls+00 1&rank=1 (Accessed May 31, 2013).
98. Schultz, H.; Weiss, J.P. The bactericidal/permeability-increasing protein (BPI) in infection and inflammatory disease. Clin. Chim. Acta, 2007, 384, 12-23.
99. Domingues, M. M; Santos, N.C.; Castanho, M.A. Antimicrobial peptide rBPI21: a translational overview from bench to clinical studies. Curr. Protein Pept. Sci., 2012, 13, 611-619.
100. ClinicalTrials. gov. A service of the U. S National Institutes of Health. http: //clinicaltrials. gov/show/NCT00454155 (Accessed May 31, 2013).
101. NovaBiotics Ltd. Novaryfyn. http: //www. novabiotics. co. uk/ Novarifyn/ Index. html (Accessed May 31, 2013).
102. Ovchinnikova, T.V.; Aleshina, G.M.; Balandin, S.V.; Krasnosdembskaya, A.D.; Markelov, M.L.; Frolova, E.I.; Leonova, Y.F.; Tagaev, A.A.; Krasnodembsky, E.G.; Kokryakov, V.N. Purification and primary structure of two isoforms of arenicin, a novel antimicrobial peptide from marine polychaeta Arenicola marina. FEBS Lett., 2004, 577, 209-214.
103. Ovchinnikova, T.V.; Shenkarev, Z.O.; Nadezhdin, K.D.; Balandin, S.V.; Zhmak, M.N.; Kudelina, I.A.; Finkina, E.I.; Kokryakov, V.N.; Arseniev, A.S. Recombinant expression, synthesis, purification, and solution structure of arenicin. Biochem. Biophys. Res. Commun., 2007, 360, 156-162.
104. Andrä, J.; Jakovkin, I.; Grötzinger, J.; Hecht, O.; Krasnosdembskaya, A.D.; Goldmann, T.; Gutsmann, T.; Leippe, M. Significance of the cyclic structure and of arginine residues for the antibacterial activity of arenicin-1 and its interaction with phospholipid and lipopolysaccharide model membranes. Biochem. J., 2008, 410, 113-122.
105. Shenkarev, Z.O.; Balandin, S.V.; Trunov, K.I.; Paramonov, A.S.; Sukhanov, S.V.; Barsukov, L.I.; Arseniev, A.S.; Ovchinnikova, T.V. Molecular mechanism of action of β-hairpin antimicrobial peptide arenicin: oligomeric structure in odecylphosphocholine micelles and pore formation in planar lipid bilayers. Biochemistry, 2011, 50, 6255-6265.
106. Travkova, O.G.; Brezesinski, G. Adsorption of the antimicrobial peptide arenicin and its linear derivative to model membranes-A maximum insertion pressure study. Chem. Phy. Lipids, 2013, 167-168, 43-50.
107. Pini, A.; Falciani, C.; Mantengoli, E.; Bindi, S.; Brunetti, J.; Iozzi, S.; Rossolini, G.M.; Bracci, L. A novel tetrabranched antimicrobial peptide that neutralizes bacterial lipopolysaccharide and prevents septic shock in vivo. FASEB J., 2010, 24, 1015-1022.
108. Pini, A.; Giuliani, A.; Falciani, C.; Runci, Y.; Ricci, C.; Lelli, B.; Malossi, M.; Neri, P.; Rossolini, G.M.; Bracci, L. Antimicrobial activity of novel dendrimeric peptides obtained by phage display selection and rational modification. Antimicrob. Agents Chemother., 2005, 49, 2665-2672.
109. Pini, A.; Giuliani, A.; Falciani, C.; Fabbrini, M.; Pileri, S.; Lelli, B.; Bracci, L. Characterization of the branched antimicrobial peptide M6 by analyzing its mechanism of action and in vivo toxicity. J. Pept. Sci., 2007, 13, 393-399.
110. Falciani, C.; Lozzi, L.; Pollini, S.; Luca, V.; Carnicelli, V.; Brunetti, J.; Lelli, B.; Bindi, S.; Scali, S.; Di Giulio, A.; Rossolini, G.M.; Mangoni, M.L.; Bracci, L.; Pini, A. Isomerization of an antimicrobial peptide broadens antimicrobial spectrum to gram-positive bacterial pathogens. PLoS One, 2012, 7, 46259.
111. Pini, A.; Lozzi, L.; Bernini, A.; Brunetti, J.; Falciani, C.; Scali, S.; Bindi, S.; Di Maggio, T.; Rossolini, G.M.; Niccolai, N.; Bracci, L. Efficacy and toxicity of the antimicrobial peptide M33 produced with different counter-ions. Amino Acids, 2012, 43, 467-473.
112. Myhrman, E.; Håkansson, J.; Lindgren, K.; Björn, C.; Sjöstrand, V.; Mahlapuu, M. The novel antimicrobial peptide PXL150 in the local treatment of skin and soft tissue infections. Appl. Microbiol. Biotechnol., 2013, 97, 3085-3096.
113. Boucher, H.W.; Talbot, G.H.; Benjamin, D.K. Jr; Bradley, J.; Guidos, R.J.; Jones, R.N.; Murray, B.E.; Bonomo, R.A.; Gilbert, D. Development of new drugs active against gram-negative bacilli: an update from the infectious diseases society of America. Clin. Infect. Dis., 2013, doi: 10. 1093/cid/cit152.
114. Chopra, I. The 2012 Garrod lecture: discovery of antibacterial drugs in the 21st century. J. Antimicrob. Chemother., 2013, 68, 496-505.
115. Hancock, R.E.W.; Patrzykat, A. Clinical development of cationic antimicrobial peptides: from natural to novel antibiotics. Curr. Drug Targets, Infect. Disord., 2002, 2, 79-83.
116. Trotti, A.; Garden, A.; Warde, P.; Symonds, P.; Langer, C.; Redman, R.; Pajak, T.F.; Fleming, T.R.; Henke, M.; Bourhis, J.; Rosenthal, D.I.; Junor, E.; Cmelak, A.; Sheehan, F.; Pulliam, J.; Devitt-Risse, P.; Fuchs, H.; Chambers, M.; O'Sullivan, B.; Ang, K.K. A multinational, randomized phase III trial of iseganan HCl oral solution for reducing the severity of oral mucositis in patients receiving radiotherapy for head-and-neck malignancy. Int. J. Radiat. Oncol. Biol. Phys., 2004, 58, 674-681.
117. Bergen, P.J.; Landersdorfer, C.B.; Lee, H.J.; Li, J.; Nation, R.L. 'Old' antibiotics for emerging multidrug-resistant bacteria. Curr. Opin. Infect. Dis., 2012, 25, 626-633.