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Polyvinyl alcohol nanofiber formulation of the designer antimicrobial peptide APO sterilizes Acinetobacter baumannii-infected skin wounds in mice

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Abstract

Native and designer cationic antimicrobial peptides are increasingly acknowledged as host defense molecules rather than true antimicrobials. Due to their ability to activate the innate immune system, these structures are used to treat uninfected and bacterially-infected wounds, including those harboring Acinetobacter baumannii. Previously we documented that when administered intramuscularly or topically in liquid formulations, the proline-rich host defense peptide dimer A3-APO accelerates uninfected wound re-epithelization and eliminates systemic and local A. baumannii, methicillin-resistant Staphylococcus aureus and other pathogen load from infected lesions better than conventional antibiotics. In the current study we sought to produce and characterize a novel delivery system, suitable for immediate and convenient application in non-hospital environments. The APO monomer was incorporated into polyvinyl alcohol nanofibers and the complex was polymerized into a solid patch dressing. Mice were subjected to skin abrasion where the wounds were either left uninfected or were inoculated with a near lethal dose of multidrug resistant A. baumannii strain. Analyzed after 3 days, APO monomer-containing patches improved wound appearance significantly better than polymer patches without antibiotics. When compared to colistin, the APO patches accelerated wound healing, and statistically significantly reduced wound size and wound bacterial load. The in vivo antimicrobial effect was more extensive than after intramuscular administration of the peptide drug, by using only one tenth of the active pharmaceutical ingredient. These data suggest that the APO monomer-impregnated nanofiber dressing can be developed as an economical first-line treatment option to skin injuries in general and battlefield burn and blast injuries in particular.

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Abbreviations

AMP:

Antimicrobial peptide

API:

Active pharmaceutical ingredient

APO:

All peptides optimized, name of designer antimicrobial peptide

ESBL:

Extended β-lactamase expressing

MBL:

Metallo-β-lactamase producing

MDR:

Multidrug-resistant

PVA:

Polyvinyl alcohol

UPLC:

Ultra performance liquid chromatography

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Acknowledgments

Part of the work reported was supported by an ARC Discovery Project Grant (DP150103522) to JDW who is also an NHMRC (Australia) Principal Research Fellow and Akhter Hossain. WL is the recipient of an MIRS PhD award. Research at the FINMH was also supported by the Victorian Government’s Operational Infrastructure Support Program.

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Authors and Affiliations

  1. University Pharmacy Department of Pharmacy Administration, Semmelweis University, Hogyes Endre Street 7-9, Budapest, 1092, Hungary

    Istvan Sebe & Romana Zelko

  2. Institute of Medical Microbiology, Semmelweis University, Nagyvarad ter 4, Budapest, 1089, Hungary

    Eszter Ostorhazi, Aron Fekete, Dora Szabo & Laszlo Otvos Jr.

  3. Department of Laboratory Medicine, Semmelweis University, Nagyvarad ter 4, Budapest, 1089, Hungary

    Eszter Ostorhazi

  4. Department of Polymer Engineering, Faculty of Mechanical Engineering, Budapest University of Technology and Economics, Muegyetem rkp. 3., Budapest, 1111, Hungary

    Krisztian N. Kovacs

  5. 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Ulloi ut 26, Budapest, 1085, Hungary

    Ilona Kovalszky

  6. Florey Institute of Neuroscience and Mental Health, University of Melbourne, 3010, Melbourne, VIC, Australia

    Wenyi Li & John D. Wade

  7. OLPE, LLC, 801 Mockingbird Lane, Audubon, PA, 19403, USA

    Laszlo Otvos Jr.

Authors
  1. Istvan Sebe
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  2. Eszter Ostorhazi
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  5. Romana Zelko
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  6. Ilona Kovalszky
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  7. Wenyi Li
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  8. John D. Wade
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  9. Dora Szabo
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  10. Laszlo Otvos Jr.
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Correspondence to Laszlo Otvos Jr..

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Conflict of interest

Dr. Laszlo Otvos is the inventor of a composition of matter patent covering the peptide APO monomer (owned by Temple University).

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Sebe, I., Ostorhazi, E., Fekete, A. et al. Polyvinyl alcohol nanofiber formulation of the designer antimicrobial peptide APO sterilizes Acinetobacter baumannii-infected skin wounds in mice. Amino Acids 48, 203–211 (2016). https://doi.org/10.1007/s00726-015-2080-4

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