Branched tetrameric lactoferricin peptides modified with diaminopropionic acid exhibit potent antimicrobial and wound-healing activities

URN to cite this document:: urn:nbn:de:bvb:355-epub-782517
DOI to cite this document:: 10.5283/epub.78251

Vavilthota, Nikitha ; Babuççu, Gizem ; Cordfunke, Robert A. ; de Boer, Leonie ; Balraadjsing, Payal ; Boekema, Bouke K. H. L. ; Drijfhout, Jan W. ; Riool, Martijn

; Zaat, Sebastian A. J.

License: Creative Commons Attribution 4.0
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Date of publication of this fulltext: 03 Dec 2025 06:16

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Abstract

Introduction: Infected chronic wounds present a dual therapeutic challenge, requiring both the eradication of pathogens and the restoration of tissue homeostasis. Often the current treatments are ineffective against multidrug-resistant (MDR) pathogens and fail to promote wound healing. Antimicrobial peptides, such as bovine lactoferricin (LfcinB), offer a promising alternative owing to their broad-spectrum activity and immunomodulatory properties. The branched tetrameric LfcinB-derived peptide (LBT; (RRWQWR)4K2Ahx2-C2) is particularly attractive, as its multivalent architecture enhances antimicrobial potency and provides a tunable branching core for structural modifications.
Methods: In this study, three novel tetrameric variants were designed by substituting the L-lysine branching residues in LBT with non-natural lysine derivatives to alter motif orientation and linker flexibility. Among the novel peptides, the diaminopropionic acid (DAP)-modified variant, (LBT-1; (RRWQWR)4DAP2Ahx2-C2) was selected as best-performing candidate based on antimicrobial and hemolytic activity assessment.
Results: Compared to LBT, the novel LBT-1 demonstrated superior activity against methicillin-resistant Staphylococcus aureus (MRSA) and MDR Acinetobacter baumannii, achieving rapid bactericidal action within 5 minutes. LBT-1 also exhibited potent activity across the ESKAPE(E) panel and against the emerging MDR fungal pathogen Candidozyma auris. Beyond direct antimicrobial effects, LBT-1 enhanced macrophage-mediated bacterial clearance, neutralized endotoxins, and accelerated wound closure in vitro. Importantly, LBT-1 showed superior pro-angiogenic activity in vitro and achieved significantly higher bactericidal activity against MRSA in an ex vivo human skin wound infection model. This study identifies LBT-1 as a multifunctional therapeutic that addresses key pathological features of chronic wounds.
Conclusion: Together, these findings validate our peptide design strategy, revealing previously unknown characteristics of the LBT peptide and the enhanced multifunctionality achieved with LBT-1, supporting its continued development for chronic wound management.

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