Abstract
Host defense peptides are preferably administered as topical therapeutic agents. We have investigated whether peptide A3-APO can enter the circulation when applied to the ear skin. Efficacy of peptide monotherapy as transdermal administration option was assessed in a systemic mouse Acinetobacter baumannii model. A3-APO reduced mortality and demonstrated a statistically significant reduction of blood bacterial counts, regardless whether it was administered prior or after bacterial challenge. The peptidic metabolite of A3-APO was efficacious when applied to the ear or tail.
References
Altemus M, Rao B, Dhabhar FS, Ding W, Granstein RD (2001) Stress-induced changes in skin barrier function in healthy women. J Invest Dermatol 117:309–317
Boucaud A, Machet L, Arbeille B, Machet MC, Sournac M, Mavon A, Patat F, Vaillant L (2001) In vitro study of low-frequency ultrasound-enhanced transdermal transport of fentanyl and caffeine across human and hairless rat skin. Int J Pharm 228:69–77
Bush K, Macielag M, Weidner-Wells M (2004) Taking inventory: antibacterial agents currently at or beyond Phase I. Curr Opin Microbiol 7:466–476
Gautam A, Nanda JS, Samuel JS, Kumari M, Priyanka P, Bedi G, Nath SK, Mittal G, Khatri N, Raghava GP (2016) Topical delivery of protein and peptide using novel cell penetrating peptide IMT-P8. Sci Rep 6:26278
Hamza M, Tohid H, Maibach H (2015) Shaving effects on percutaneous penetration: clinical implications. Cutan Ocul Toxicol 234:335–343
Heunis TD, Smith C, Dicks LM (2013) Evaluation of a nisin-eluting nanofiber scaffold to treat Staphylococcus aureus-induced skin infections in mice. Antimicrob Agents Chemother 57:3928–3935
Hilchie AL, Wuerth K, Hancock RE (2013) Immune modulation by multifaceted cationic host defense (antimicrobial) peptides. Nat Chem Biol 9:761–768
Ita KB (2015) Chemical penetration enhancers for transdermal drug delivery—success and challenges. Curr Drug Deliv 12:645–651
Katikaneni S (2015) Transdermal delivery of biopharmaceuticals: dream or reality? Ther Deliv 6:1109–1116
Merens A, Rapp C, Delaune D, Danis J, Berger F, Michel R (2014) Prevention of combat-related infections: antimicrobial therapy in battlefield and barrier measures in French military medical treatment facilities. Travel Med Infect Dis 12:318–329
Mishell DR Jr (1996) Pharmacokinetics of depot medroxyprogesterone acetate contraception. J Reprod Med 41(5 Suppl):381–390
Noto PB, Abbadessa G, Cassone M, Mateo GD, Agelan A, Wade JD, Szabo D, Kocsis B, Nagy K, Rozgonyi F, Otvos L Jr (2008) Alternative stabilities of a proline-rich antibacterial peptide in vitro and in vivo. Protein Sci 17:1249–1255
Ostorhazi E, Rozgonyi F, Sztodola A, Harmos F, Kovalszky I, Szabo D, Knappe D, Hoffmann R, Cassone M, Wade JD, Bonomo RA, Otvos L Jr (2010) Preclinical advantages of intramuscularly administered peptide A3-APO over existing therapies in Acinetobacter baumannii wound infections. J Antimicrob Chemother 65:2416–2422
Ostorhazi E, Rozgonyi F, Szabo D, Binas A, Cassone M, Wade JD, Nolte O, Bethel CR, Bonomo RA, Otvos L Jr (2011) Intramuscularly administered peptide A3-APO is effective against carbapenem-resistant Acinetobacter baumannii in mouse models of systemic infections. Biopolymers 96:126–129
Ostorhazi E, Voros E, Nemes-Nikodem E, Pinter D, Sillo P, Mayer B, Wade JD, Otvos L Jr (2013) Rapid systemic and local treatments with the antibacterial peptide dimer A3-APO and its monomeric metabolite eliminate bacteria and reduce inflammation in intradermal lesions infected with Propionibacterium acnes and meticillin-resistant Staphylococcus aureus. Int J Antimicrob Agents 42:537–543
Ostorhazi E, Nemes-Nikodem É, Knappe D, Hoffmann R (2014) In vivo activity of optimized apidaecin and oncocin peptides against a multiresistant, KPC-producing Klebsiella pneumoniae strain. Protein Pept Lett 21:368–373
Otvos L Jr, Cudic M, Chua BY, Deliyannis G, Jackson DC (2004) An insect antibacterial peptide-based drug delivery system. Mol Pharm 1:220–232
Patra S, Roy E, Madhuri R, Sharma PK (2016) The next generation cell-penetrating peptide and carbon dot conjugated nano-liposome for transdermal delivery of curcumin. Biomater Sci 4:418–429
Schmidt R, Ostorhazi E, Wende E, Knappe D, Hoffmann R (2016) Pharmacokinetics and in vivo efficacy of optimized oncocin derivatives. J Antimicrob Chemother 71:1003–1011
Sebe I, Ostorhazi E, Fekete A, Kovacs KN, Zelko R, Kovalszky I, Li W, Wade JD, Szabo D, Otvos L Jr (2016) Polyvinyl alcohol nanofiber formulation of the designer antimicrobial peptide APO sterilizes Acinetobacter baumannii-infected skin wounds in mice. Amino Acids 48:203–211
Simsek T, Simsek HU, Canturk NZ (2014) Response to trauma and metabolic changes: posttraumatic metabolism. Ulus Cerrahi Derg 30:153–159
Steinstraesser L, Hirsch T, Schulte M, Kueckelhaus M, Jacobsen F, Mersch EA, Stricker I, Afacan N, Jenssen H, Hancock RE, Kindrachuk J (2012) Innate defense regulator peptide 1018 in wound healing and wound infection. PLoS One 7:e39373
Summerfield A, Meurens F, Ricklin ME (2014) The immunology of the porcine skin and its value as a model for human skin. Mol Immunol 66:14–21
Tien HC, Battad A, Bryce EA, Fuller J, Mulvey M, Bernard K, Brisebois R, Doucet JJ, Rizoli SB, Fowler R, Simor A (2007) Multi-drug resistant Acinetobacter infections in critically injured Canadian forces soldiers. BMC Infect Dis 7:95
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The authors wish to thank Dr. Carl Kraus for critical reading of the manuscript.
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Dr. Laszlo Otvos is the inventor of a composition of matter patent covering the APO peptide monomer (owned by Temple University) licensed to Arrevus, Inc. Dr. Otvos is a scientific advisor to Arrevus.
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All procedures performed in studies involving animals were in accordance with the ethical standards of Semmelweis University.
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Ostorhazi, E., Horvath, A., Szabo, D. et al. Transdermally administered proline–arginine-rich host defense peptides show systemic efficacy in a lethal mouse bacteremia model. Amino Acids 49, 1647–1651 (2017). https://doi.org/10.1007/s00726-017-2457-7
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DOI: https://doi.org/10.1007/s00726-017-2457-7