Branched tetrameric lactoferricin peptides modified with diaminopropionic acid exhibit potent antimicrobial and wound-healing activities
Frontiers in Pharmacology, vol. 16, pp. 1719557
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) 4 K 2 Ahx 2 -C 2 ) 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) 4 DAP 2 Ahx 2 -C 2 ) 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.
Authors 9
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Amsterdam University Medical Centers · Amsterdam institute for Immunology and Infectious Diseases · University of Amsterdam
Affiliation as printed
Department of Medical Microbiology and Infection Prevention, Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, Netherlands
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Amsterdam University Medical Centers · Amsterdam institute for Immunology and Infectious Diseases · University of Amsterdam
Affiliation as printed
Department of Medical Microbiology and Infection Prevention, Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, Netherlands
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Leiden University · Leiden University Medical Center
Affiliation as printed
Department of Immunology, Leiden University Medical Centre, Leiden, Netherlands
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Amsterdam University Medical Centers · Amsterdam institute for Immunology and Infectious Diseases · University of Amsterdam
Affiliation as printed
Department of Medical Microbiology and Infection Prevention, Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, Netherlands
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Amsterdam University Medical Centers · Amsterdam institute for Immunology and Infectious Diseases · University of Amsterdam
Affiliation as printed
Department of Medical Microbiology and Infection Prevention, Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, Netherlands
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Association of Dutch Burn Centres · Amsterdam University Medical Centers · Amsterdam Movement Sciences
Affiliation as printed
Burn Research Lab, Alliance of Dutch Burn Care, Beverwijk, Netherlands
Department of Plastic, Reconstructive and Hand Surgery, Tissue Function and Regeneration, Amsterdam Movement Sciences Research Institute, Amsterdam University Medical Centre, Amsterdam, Netherlands
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Leiden University · Leiden University Medical Center
Affiliation as printed
Department of Immunology, Leiden University Medical Centre, Leiden, Netherlands
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University Hospital Regensburg · Amsterdam University Medical Centers · Amsterdam institute for Immunology and Infectious Diseases · University of Amsterdam
Affiliation as printed
Department of Medical Microbiology and Infection Prevention, Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, Netherlands
Laboratory for Experimental Trauma Surgery, Department of Trauma Surgery, University Hospital Regensburg, Regensburg, Germany
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Amsterdam University Medical Centers · Amsterdam institute for Immunology and Infectious Diseases · University of Amsterdam
Affiliation as printed
Department of Medical Microbiology and Infection Prevention, Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, Netherlands
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