The Combination of Synoeca-MP Antimicrobial Peptide with IDR-1018 Stimulates Proliferation, Migration, and the Expression of Pro-Regenerative Genes in Both Human Skin Cell Cultures and 3D Skin Equivalents

Abstract

In skin lesions, the development of microbial infection affects the healing process, increasing morbidity and mortality rates in patients with severe burns, diabetic foot, and other types of skin injuries. Synoeca-MP is an antimicrobial peptide (AMP) that exhibits activity against several bacteria of clinical importance, but its cytotoxicity can represent a problem for its positioning as an effective antimicrobial compound. In contrast, the immunomodulatory peptide IDR-1018 presents low toxicity and a wide regenerative potential due to its ability to reduce apoptotic mRNA expression and promote skin cell proliferation. In the present study, we used human skin cells and a 3D skin equivalent models to analyze the potential of the IDR-1018 peptide to attenuate the cytotoxicity of synoeca-MP, as well as the influence of synoeca-MP/IDR-1018 combination on cell proliferation, regenerative processes, and wound repair. We found that the addition of IDR-1018 significantly improved the biological properties of synoeca-MP on skin cells without modifying its antibacterial activity against S. aureus. Likewise, in both melanocytes and keratinocytes, the treatment with synoeca-MP/IDR-1018 combination induces cell proliferation and migration, while in a 3D human skin equivalent model, it can accelerate wound reepithelization. Furthermore, treatment with this peptide combination generates an up-regulation in the expression of pro-regenerative genes in both monolayer cell cultures and in 3D skin equivalents. This data suggests that the synoeca-MP/IDR-1018 combination possesses a good profile of antimicrobial and pro-regenerative activity, opening the door to the development of new strategies for the treatment of skin lesions.

Screening of the Skin-Regenerative Potential of Antimicrobial Peptides: Clavanin A, Clavanin-MO, and Mastoparan-MO

“…In this sense, it has also been observed that some antimicrobial peptides, such as the synthetic A-hBD-2 or the LL-37 peptide (the only member of the human cathelicidin family), have the ability to facilitate the wound healing process by stimulating cell migration in both skin cells and mesenchymal stem cells [14,22]. Likewise, Synoeca-MP, an AMP with a broad antimicrobial spectrum, has also been shown to be useful in skin repair when combined with host-defense peptides IDR-1018 [23].…”

“…The proregenerative potential of various AMPs is associated with their ability to modulate the inflammation process, which is key in the restoration of normal tissue architecture during wound repair [36]. Peptides such as IDR-1018, which exert their action through regulation of the inflammatory response, can induce the repair of skin wounds [13,23,37]. It has been observed that both Clavanin A and Mastoparan-MO are capable of modulating innate immunity by stimulating leukocyte recruitment to the site of infection and production of immune mediators GM-CSF, IFN-γ, and MCP-1 while suppressing excessive inflammatory response by increasing the synthesis of anti-inflammatory cytokines such as IL-10 and repressing the levels of proinflammatory cytokines IL-6, IL-12, and TNF-α.…”

Exploring Skin Wound Healing Models and the Impact of Natural Lipids on the Healing Process

“…These models incorporate multiple cell types and layers, including keratinocytes, fibroblasts, and sometimes immune cells, closely recapitulating the microenvironment of a healing wound. The inclusion of ECM components in these models enhances their physiological relevance, making them valuable tools for studying aspects such as tissue regeneration and re-epithelialization [47,48].…”

Editorial: Antimicrobial peptides and their druggability, bio-safety, stability, and resistance

“…The combination of cecropin D-derived peptide and caspofungin showed the synergistic effects against Candida albicans ( Guevara-Lora et al ). The study of Alencar-Silva et al ( 2023 ) demonstrated the decreased cytotoxicity of Synoeca MP through its combination with IDR-1018. The combination also enhanced cell proliferation and migration and accelerated wound re-epithelialization, which opens the possibility for the development of new strategies in treatment of skin injuries (Alencar-Silva et al, 2023 ).…”