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Abstract

As growing numbers of patients are at higher risk of infection, novel topical broad-spectrum antimicrobials are urgently required for wound infection management. Robust pre-clinical studies should support the development of such novel antimicrobials.

To date, evidence of robust investigation of the cytotoxicity and antimicrobial spectrum of activity of antimicrobial peptides (AMP)s is lacking in published literature. Using a more clinical lens, we address this gap in experimental approach, building on our experience with poly--lysine (PLL)-based AMP polymers.

To evaluate the bactericidal activity and cytotoxicity of a PLL-based 16-armed star AMP polymer, designated 16-PLL, as a novel candidate antimicrobial.

Antimicrobial susceptibilities of clinical isolates and reference strains of ESKAPE ( spp., , spp.) pathogens, to 16-PLL were investigated. Human erythrocyte haemolysis and keratinocyte viability assays were used to assess toxicity. Modifications were made to 16-PLL and re-evaluated for improvement.

Minimum bactericidal concentration of 16-PLL ranged from 1.25 µM to ≥25 µM. At 2.5 µM, 16-PLL was broadly bactericidal against ESKAPE strains/wound isolates. Log-reduction in colony forming units (c.f.u.) per millilitre after 1 h, ranged from 0.3 () to 5.6 (). At bactericidal concentrations, 16-PLL was toxic to human keratinocyte and erythrocytes. Conjugates of 16-PLL, Trifluoroacetylated (TFA)−16-PLL, and Poly-ethylene glycol (PEG)ylated 16-PLL, synthesised to address toxicity, only moderately reduced cytotoxicity and haemolysis.

Due to poor selectivity indices, further development of 16-PLL is unlikely warranted. However, considering the unmet need for novel topical antimicrobials, the ease of AMP polymer synthesises/modification is attractive. To support more rational development, prioritising clinically relevant pathogens and human cells, to establish selective toxicity profiles , is critical. Further characterisation and discovery utilising artificial intelligence and computational screening approaches can accelerate future AMP nanomaterial development.

Funding
This study was supported by the:
  • British Infection Association (Award 300921)
    • Principle Award Recipient: AaronDoherty
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License. This article was made open access via a Publish and Read agreement between the Microbiology Society and the corresponding author’s institution.
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2024-09-13
2024-12-13
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References

  1. Antimicrobial Resistance Collaborators Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet 2022; 399:629–655 [View Article] [PubMed]
    [Google Scholar]
  2. Bader MS. Diabetic foot infection. Am Fam Physician 2008; 78:71–79 [PubMed]
    [Google Scholar]
  3. Senneville É, Albalawi Z, van SA, Abbas ZG, Allison G et al. IWGDF/IDSA guidelines on the diagnosis and treatment of diabetes-related foot infections (IWGDF/IDSA 2023). Clin Infect Dis 2023ciad527 [View Article]
    [Google Scholar]
  4. Surgical site infections: prevention and treatment. London: National Institute for Health and Care Excellence (NICE). (NICE Guideline, No. 125); n.d https://www.ncbi.nlm.nih.gov/books/NBK542473 accessed 22 May 2024 [PubMed]
  5. WHO Prevention and Management of Wound Infection Guideline, second edition. Geneva: World Health Organisation; 2018 https://www.who.int/publications/i/item/prevention-and-management-of-wound-infection accessed 22 May 2024
  6. Shen W, He P, Xiao C, Chen X. From antimicrobial peptides to antimicrobial poly(α-amino acid)s. Adv Healthc Mater 2018; 7:e1800354 [View Article] [PubMed]
    [Google Scholar]
  7. Shai Y. Mechanism of the binding, insertion and destabilization of phospholipid bilayer membranes by alpha-helical antimicrobial and cell non-selective membrane-lytic peptides. Biochim Biophys Acta 1999; 1462:55–70 [View Article] [PubMed]
    [Google Scholar]
  8. Matsuzaki K. Why and how are peptide-lipid interactions utilized for self-defense? Magainins and tachyplesins as archetypes. Biochim Biophys Acta 1999; 1462:1–10 [View Article] [PubMed]
    [Google Scholar]
  9. Yang L, Weiss TM, Lehrer RI, Huang HW. Crystallization of antimicrobial pores in membranes: magainin and protegrin. Biophys J 2000; 79:2002–2009 [View Article] [PubMed]
    [Google Scholar]
  10. Patil NA, Kandasubramanian B. Functionalized polylysine biomaterials for advanced medical applications: a review. Eur Polym J 2021; 146:110248 [View Article]
    [Google Scholar]
  11. Ramamurthy R, Mehta CH, Nayak UY. Structurally nanoengineered antimicrobial peptide polymers: design, synthesis and biomedical applications. World J Microbiol Biotechnol 2021; 37:139 [View Article] [PubMed]
    [Google Scholar]
  12. Zheng M, Pan M, Zhang W, Lin H, Wu S et al. Poly(α-l-lysine)-based nanomaterials for versatile biomedical applications: current advances and perspectives. Bioact Mater 2021; 6:1878–1909 [View Article] [PubMed]
    [Google Scholar]
  13. Lu C, Quan G, Su M, Nimmagadda A, Chen W et al. Molecular architecture and charging effects enhance the in vitro and in vivo performance of multi‐arm antimicrobial agents based on star‐shaped poly(l‐lysine). Adv Ther 2019; 2:1900147 [View Article]
    [Google Scholar]
  14. Lam SJ, O’Brien-Simpson NM, Pantarat N, Sulistio A, Wong EHH et al. Combating multidrug-resistant Gram-negative bacteria with structurally nanoengineered antimicrobial peptide polymers. Nat Microbiol 2016; 1:16162 [View Article] [PubMed]
    [Google Scholar]
  15. Walsh DP, Murphy RD, Panarella A, Raftery RM, Cavanagh B et al. Bioinspired star-shaped poly(l-lysine) polypeptides: efficient polymeric nanocarriers for the delivery of DNA to mesenchymal stem cells. Mol Pharm 2018; 15:1878–1891 [View Article] [PubMed]
    [Google Scholar]
  16. Grace A, Murphy R, Dillon A, Smith D, Cryan S-A et al. Modified poly(L-lysine)-based structures as novel antimicrobials for diabetic foot infections, an in-vitro study. HRB Open Res 2022; 5:4 [View Article] [PubMed]
    [Google Scholar]
  17. Walsh DP, Raftery RM, Murphy R, Chen G, Heise A et al. Gene activated scaffolds incorporating star-shaped polypeptide-pDNA nanomedicines accelerate bone tissue regeneration in vivo. Biomater Sci 2021; 9:4984–4999 [View Article] [PubMed]
    [Google Scholar]
  18. Byrne M, Victory D, Hibbitts A, Lanigan M, Heise A et al. Molecular weight and architectural dependence of well-defined star-shaped poly(lysine) as a gene delivery vector. Biomater Sci 2013; 1:1223–1234 [View Article] [PubMed]
    [Google Scholar]
  19. Miles AA, Misra SS, Irwin JO. The estimation of the bactericidal power of the blood. J Hyg 1938; 38:732–749 [View Article] [PubMed]
    [Google Scholar]
  20. Zapotoczna M, Forde É, Hogan S, Humphreys H, O’Gara JP et al. Eradication of Staphylococcus aureus biofilm infections using synthetic antimicrobial peptides. J Infect Dis 2017; 215:975–983 [View Article] [PubMed]
    [Google Scholar]
  21. Oren Z, Shai Y. Mode of action of linear amphipathic alpha-helical antimicrobial peptides. Biopolymers 1998; 47:451–463 [View Article]
    [Google Scholar]
  22. Lipsky BA, Holroyd KJ, Zasloff M. Topical versus systemic antimicrobial therapy for treating mildly infected diabetic foot ulcers: a randomized, controlled, double-blinded, multicenter trial of pexiganan cream. Clin Infect Dis 2008; 47:1537–1545 [View Article] [PubMed]
    [Google Scholar]
  23. Silverman MH. Pexiganan versus placebo control for the treatment of mild infections of diabetic foot ulcers. A randomized, double-blind, multicenter, superiority, placebo-controlled phase 3 study of pexiganan cream 0.8% applied twice daily for 14 days in the treatment of adults with mild infections of diabetic foot ulcers. Available from https://clinicaltrials.gov/ct2/show/record/NCT01590758
  24. Ge C, Yang J, Duan S, Liu Y, Meng F et al. Fluorinated α-helical polypeptides synchronize mucus permeation and cell penetration toward highly efficient pulmonary siRNA delivery against acute lung injury. Nano Lett 2020; 20:1738–1746 [View Article] [PubMed]
    [Google Scholar]
  25. Wu T, Wang L, Ding S, You Y. Fluorinated PEG‐polypeptide polyplex micelles have good serum‐resistance and low cytotoxicity for gene delivery. Macromol Biosci 2017; 17: [View Article]
    [Google Scholar]
  26. Morris CJ, Beck K, Fox MA, Ulaeto D, Clark GC et al. Pegylation of antimicrobial peptides maintains the active peptide conformation, model membrane interactions, and antimicrobial activity while improving lung tissue biocompatibility following airway delivery. Antimicrob Agents Chemother 2012; 56:3298–3308 [View Article] [PubMed]
    [Google Scholar]
  27. Veronese FM, Harris JM. Introduction and overview of peptide and protein pegylation. Adv Drug Deliv Rev 2002; 54:453–456 [View Article]
    [Google Scholar]
  28. Greco I, Molchanova N, Holmedal E, Jenssen H, Hummel BD et al. Correlation between hemolytic activity, cytotoxicity and systemic in vivo toxicity of synthetic antimicrobial peptides. Sci Rep 2020; 10:13206 [View Article]
    [Google Scholar]
  29. Ruiz Puentes P, Henao MC, Cifuentes J, Muñoz-Camargo C, Reyes LH et al. Rational discovery of antimicrobial peptides by means of artificial intelligence. Membranes 2022; 12:708 [View Article] [PubMed]
    [Google Scholar]
  30. Haney EF, Straus SK, Hancock REW. Reassessing the host defense peptide landscape. Front Chem 2019; 7:43 [View Article] [PubMed]
    [Google Scholar]
  31. Zarrintaj P, Ghorbani S, Barani M, Singh Chauhan NP, Khodadadi Yazdi M et al. Polylysine for skin regeneration: a review of recent advances and future perspectives. Bioeng Transl Med 2022; 7:e10261 [View Article] [PubMed]
    [Google Scholar]
  32. Haney EF, Brito-Sánchez Y, Trimble MJ, Mansour SC, Cherkasov A et al. Computer-aided discovery of peptides that specifically attack bacterial biofilms. Sci Rep 2018; 8:1871 [View Article]
    [Google Scholar]
  33. Mookherjee N, Anderson MA, Haagsman HP, Davidson DJ. Antimicrobial host defence peptides: functions and clinical potential. Nat Rev Drug Discov 2020; 19:311–332 [View Article]
    [Google Scholar]
  34. de la Fuente-Núñez C, Hancock REW. Using anti-biofilm peptides to treat antibiotic-resistant bacterial infections. Postdoc J 2015; 3:1–8 [View Article] [PubMed]
    [Google Scholar]
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