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In vitro and in vivo antibacterial properties of peptide AMC-109 impregnated wound dressings and gels

The Journal of Antibiotics volume 74, pages 337–345 (2021)Cite this article

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Abstract

Synthetic mimics of antimicrobial peptides (AMPs) is a promising class of molecules for a variety of antimicrobial applications. Several hurdles must be passed before effective systemic infection therapies with AMPs can be achieved, but the path to effective topical treatment of skin, nail, and soft tissue infections appears less challenging to navigate. Skin and soft tissue infection is closely coupled to the emergence of antibiotic resistance and represents a major burden to the healthcare system. The present study evaluates the promising synthetic cationic AMP mimic, AMC-109, for treatment of skin infections in vivo. The compound is evaluated both in impregnated cotton wound dressings and in a gel formulation against skin infections caused by Staphylococcus aureus and methicillin resistant S. aureus. Both the ability to prevent colonization and formation of an infection, as well as eradicate an ongoing infection in vivo with a high bacterial load, were evaluated. The present work demonstrates that AMC-109 displays a significantly higher antibacterial activity with up to a seven-log reduction in bacterial loads compared to current clinical standard therapy; Altargo cream (1% retapamulin) and Fucidin cream (2% fusidic acid) in the in vivo wound models. It is thus concluded that AMC-109 represents a promising entry in the development of new and effective remedies for various skin infections.

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References

  1. Fernandes P, Martens E. Antibiotics in late clinical development. Biochem Pharm. 2017;133:152–63.

    Article  CAS  PubMed  Google Scholar 

  2. Tacconelli E, et al. Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis. 2018;18:318–27.

    Article  PubMed  Google Scholar 

  3. Cassini A, et al. Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: a population-level modelling analysis. Lancet Infect Dis. 2019;19:56–66.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Founou RC, Founou LL, Essack SY. Clinical and economic impact of antibiotic resistance in developing countries: a systematic review and meta-analysis. PLoS ONE. 2017;12:e0189621.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Tacconelli E, Pezzani MD. Public health burden of antimicrobial resistance in Europe. Lancet Infect Dis. 2019;19:4–6.

    Article  PubMed  Google Scholar 

  6. Dadgostar P. Antimicrobial resistance: implications and costs. Infect Drug Resist. 2019;12:3903–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hofer U. The cost of antimicrobial resistance. Nat Rev Microbiol. 2019;17:3.

    Article  CAS  PubMed  Google Scholar 

  8. Zasloff M. Antimicrobial peptides of multicellular organisms. Nature. 2002;415:389–95.

    Article  CAS  PubMed  Google Scholar 

  9. Mahlapuu M, Håkansson J, Ringstad L, Björn C. Antimicrobial peptides: an emerging category of therapeutic agents. Front Cell Infect Microbiol. 2016;6:194.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Yeaman MR, Yount NY. Mechanisms of antimicrobial peptide action and resistance. Pharmacol Rev. 2003;55:27–55.

    Article  CAS  PubMed  Google Scholar 

  11. Svendsen JSM, Grant TM, Rennison D, Brimble MA, Svenson J. Very short and stable lactoferricin-derived antimicrobial peptides: design principles and potential uses. Acc Chem Res. 2019;52:749–59.

    Article  CAS  PubMed  Google Scholar 

  12. Molchanova N, Hansen PR, Franzyk H. Advances in development of antimicrobial peptidomimetics as potential drugs. Molecules. 2017;22:1430.

    Article  PubMed Central  Google Scholar 

  13. Strøm MB, et al. The pharmacophore of short cationic antibacterial peptides. J Med Chem. 2003;46:1567–70.

    Article  PubMed  Google Scholar 

  14. Flaten GE, et al. In vitro characterization of human peptide transporter hPEPT1 interactions and passive permeation studies of short cationic antimicrobial peptides. J Med Chem. 2011;54:2422–32.

    Article  CAS  PubMed  Google Scholar 

  15. Svenson J, et al. Altered activity and physicochemical properties of short cationic antimicrobial peptides by incorporation of arginine analogues. Mol Pharm. 2009;6:996–1005.

    Article  CAS  PubMed  Google Scholar 

  16. Karstad R, et al. Targeting the S1 and S3 subsite of trypsin with unnatural cationic amino acids generates antimicrobial peptides with potential for oral administration. J Med Chem. 2012;55:6294–305.

    Article  CAS  PubMed  Google Scholar 

  17. Svenson J, et al. Antimicrobial peptides with stability toward tryptic degradation. Biochemistry. 2008;47:3777–88.

    Article  CAS  PubMed  Google Scholar 

  18. Svenson J, et al. Metabolic fate of lactoferricin-based antimicrobial peptides: effect of truncation and incorporation of amino acid analogs on the in vitro metabolic stability. J Pharm Exp Ther. 2010;332:1032–9.

    Article  CAS  Google Scholar 

  19. Svenson J, Brandsdal BO, Stensen W, Svendsen JS. Albumin binding of short cationic antimicrobial micropeptides and its influence on the in vitro bactericidal effect. J Med Chem. 2007;50:3334–9.

    Article  CAS  PubMed  Google Scholar 

  20. Lei J, et al. The antimicrobial peptides and their potential clinical applications. Am J Transl Res. 2019;11:3919.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Mishra B, Narayana JL, Lushnikova T, Wang X, Wang G. Low cationicity is important for systemic in vivo efficacy of database-derived peptides against drug-resistant Gram-positive pathogens. Proc Natl Acad Sci. 2019;116:13517–22.

    Article  CAS  PubMed  Google Scholar 

  22. Greco I, et al. Correlation between hemolytic activity, cytotoxicity and systemic in vivo toxicity of synthetic antimicrobial peptides. Sci Rep. 2020;10:13206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Di L. Strategic approaches to optimizing peptide ADME properties. AAPS J. 2015;17:134–43.

    Article  CAS  PubMed  Google Scholar 

  24. Schauber J, Gallo RL. Antimicrobial peptides and the skin immune defense system. J Allergy Clin Immunol. 2008;122:261–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Fellermann K, Wehkamp J, Stange EF. Antimicrobial peptides in the skin. N Engl J Med. 2003;348:361–3.

    Article  PubMed  Google Scholar 

  26. 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. 2008;8:135–43.

    Article  CAS  PubMed  Google Scholar 

  27. Woodburn KW, Jaynes J, Clemens LE. Designed antimicrobial peptides for topical treatment of antibiotic resistant Acne vulgaris. Antibiotics. 2020;9:23.

    Article  CAS  PubMed Central  Google Scholar 

  28. Woodburn KW, Jaynes JM, Clemens LE. Evaluation of the antimicrobial peptide, RP557, for the broad-spectrum treatment of wound pathogens and biofilm. Front Microbiol. 2019;10:1688.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Thapa RK, Diep DB, Tønnesen HH. Topical antimicrobial peptide formulations for wound healing: current developments and future prospects. Acta Biomater. 2020;103:52–67.

    Article  CAS  PubMed  Google Scholar 

  30. Stulberg DL, Penrod MA, Blatny RA. Common bacterial skin infections. Am Fam Physician. 2002;66:119–25.

    PubMed  Google Scholar 

  31. Kaye KS, Petty LA, Shorr AF, Zilberberg MD. Current epidemiology, etiology, and burden of acute skin infections in the United States. Clin Infect Dis. 2019;68:193–9.

    Article  Google Scholar 

  32. Lee G, Boyd N, Lawson K, Frei C. Incidence and cost of skin and soft tissue infections in the United States. Value Health. 2015;18:A245.

    Article  Google Scholar 

  33. Strøm MB, et al. Important structural features of 15-residue lactoferricin derivatives and methods for improvement of antimicrobial activity. Biochem Cell Biol. 2002;80:65–74.

    Article  PubMed  Google Scholar 

  34. Haug BE, Stensen W, Kalaaji M, Rekdal Ø, Svendsen JS. Synthetic antimicrobial peptidomimetics with therapeutic potential. J Med Chem. 2008;51:4306–14.

    Article  CAS  PubMed  Google Scholar 

  35. Haug BE, Skar ML, Svendsen JS. Bulky aromatic amino acids increase the antibacterial activity of 15‐residue bovine lactoferricin derivatives. J Pep Sci. 2001;7:425–32.

    Article  CAS  Google Scholar 

  36. Haug BE, Strom M, Svendsen M. The medicinal chemistry of short lactoferricin-based antibacterial peptides. Curr Med Chem. 2007;14:1–18.

    Article  CAS  PubMed  Google Scholar 

  37. Karstad R, Isaksen G, Brandsdal B-O, Svendsen JS, Svenson J. Unnatural amino acid side chains as S1, S1′, and S2′ probes yield cationic antimicrobial peptides with stability toward chymotryptic degradation. J Med Chem. 2010;53:5558–66.

    Article  CAS  PubMed  Google Scholar 

  38. Saravolatz LD, et al. In vitro activities of LTX-109, a synthetic antimicrobial peptide, against methicillin-resistant, vancomycin-intermediate, vancomycin-resistant, daptomycin-nonsusceptible, and linezolid-nonsusceptible Staphylococcus aureus. Antimicrob Agents Chemother. 2012;56:4478–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Stensen W, et al. Short cationic antimicrobial peptides display superior antifungal activities toward candidiasis and onychomycosis in comparison with terbinafine and amorolfine. Mol Pharm. 2016;13:3595–600.

    Article  CAS  PubMed  Google Scholar 

  40. Fernandes KE, Payne RJ, Carter DA. Lactoferrin-derived peptide lactofungin is potently synergistic with amphotericin B. Antimicrob Agents Chemother. 2020;64:e00842-20

    Article  PubMed  PubMed Central  Google Scholar 

  41. Nilsson AC, et al. LTX-109 is a novel agent for nasal decolonization of methicillin-resistant and-sensitive Staphylococcus aureus. Antimicrob Agents Chemother. 2015;59:145–51.

    Article  PubMed  Google Scholar 

  42. Kugelberg E, et al. Establishment of a superficial skin infection model in mice by using Staphylococcus aureus and Streptococcus pyogenes. Antimicrob Agents Chemother. 2005;49:3435–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Scaramuzzino DA, McNiff JM, Bessen DE. Humanized in vivo model for Streptococcal impetigo. Infect Immun. 2000;68:2880–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yu G, Baeder DY, Regoes RR, Rolff J. Combination effects of antimicrobial peptides. Antimicrob Agents Chemother. 2016;60:1717–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Håkansson J, et al. Efficacy of the novel topical antimicrobial agent PXL150 in a mouse model of surgical site infections. Antimicrob Agents Chemother. 2014;58:2982–4.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Haisma EM, et al. Antimicrobial peptide P60. 4Ac-containing creams and gel for eradication of methicillin-resistant Staphylococcus aureus from cultured skin and airway epithelial surfaces. Antimicrob Agents Chemother. 2016;60:4063–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Jones V, Grey JE, Harding KG. Wound dressings. BMJ. 2006;332:777–80.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Isaksson J, et al. A synthetic antimicrobial peptidomimetic (LTX 109): stereochemical impact on membrane disruption. J Med Chem. 2011;54:5786–95.

    Article  CAS  PubMed  Google Scholar 

  49. Mortensen B, Fugelli A, Olsen W, editors. Evaluation of the preclinical safety and tolerability profile of LTX-109 a novel antimicrobial drug. Abstr 51st interscience conference on antimicrobial agents and chemotherapy. American Society for Microbiology, Boston, MA; 2011.

  50. Pfalzgraff A, Brandenburg K, Weindl G. Antimicrobial peptides and their therapeutic potential for bacterial skin infections and wounds. Front Pharmacol. 2018;9:281.

  51. Mahlapuu M, Björn C, Ekblom J. Antimicrobial peptides as therapeutic agents: opportunities and challenges. Crit Rev Biotechnol. 2020;40:978–92.

    Article  CAS  PubMed  Google Scholar 

  52. Björn C, et al. Efficacy and safety profile of the novel antimicrobial peptide PXL150 in a mouse model of infected burn wounds. Int J Antimicrob Agents. 2015;45:519–24.

    Article  PubMed  Google Scholar 

  53. Myhrman E, et al. The novel antimicrobial peptide PXL150 in the local treatment of skin and soft tissue infections. Appl Microbiol Biotechnol. 2013;97:3085–96.

    Article  CAS  PubMed  Google Scholar 

  54. Li Z, et al. K1K8: an Hp1404-derived antibacterial peptide. Appl Microbiol Biotechnol. 2016;100:5069–77.

    Article  CAS  PubMed  Google Scholar 

  55. Liu S, et al. Assessment of antimicrobial and wound healing effects of Brevinin-2Ta against the bacterium Klebsiella pneumoniae in dermally-wounded rats. Oncotarget. 2017;8:111369–85.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Jacobsen F, et al. Antimicrobial activity of the recombinant designer host defence peptide P-novispirin G10 in infected full-thickness wounds of porcine skin. J Antimicrob Chemother. 2007;59:493–8.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was partly supported by the BIA—User-driven Research-based Innovation Project Program (Grant Number 281949) from the Research Council of Norway.

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  1. Johan Svenson

    Present address: Cawthron Institute, Nelson, New Zealand

Authors and Affiliations

  1. Department of Chemistry, Biomaterial & Textile, RISE Research Institutes of Sweden, Borås, Sweden

    Joakim Håkansson & Johan Svenson

  2. Department of Laboratory Medicine, Institute of Biomedicine, Gothenburg University, Gothenburg, Sweden

    Joakim Håkansson

  3. Amicoat A/S, Sandvika, Norway

    Jorunn Pauline Cavanagh, Bjarte Mortensen & John-Sigurd Svendsen

  4. Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway

    Jorunn Pauline Cavanagh

  5. Department of Chemistry, UiT The Arctic University of Norway, Tromsø, Norway

    Wenche Stensen & John-Sigurd Svendsen

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Correspondence to Johan Svenson.

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JPC, BM, and JSS are employed by Amicoat A/S.

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All animal experiments in the present report were performed after prior approval from the local ethics committees in Gothenburg (Sweden) and Alberta, (Canada).

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Håkansson, J., Cavanagh, J.P., Stensen, W. et al. In vitro and in vivo antibacterial properties of peptide AMC-109 impregnated wound dressings and gels. J Antibiot 74, 337–345 (2021). https://doi.org/10.1038/s41429-021-00406-5

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