Abstract
Multidrug resistance bacteria constitue an increasing global health problem and the development of novel therapeutic strategies to face this challenge is urgent. Antimicrobial peptides have been proven as potent agents against pathogenic bacteria shown by promising in vitro results. The aim of this study was to characterize the antimicrobial effects of PLNC8 αβ on cell signaling pathways and inflammatory responses of human keratinocytes infected with S. aureus. PLNC8 αβ did not affect the viability of human keratinocytes but upregulated several cytokines (IL-1β, IL-6, CXCL8), MMPs (MMP1, MMP2, MMP9, MMP10) and growth factors (VEGF and PDGF-AA), which are essential in cell regeneration. S. aureus induced the expression of several inflammatory mediators at the gene and protein level and PLNC8 αβ was able to significantly suppress these effects. Intracellular signaling events involved primarily c-Jun via JNK, c-Fos and NFκB, suggesting their essential role in the initiation of inflammatory responses in human keratinocytes. PLNC8 αβ was shown to modulate early keratinocyte responses, without affecting their viability. The peptides have high selectivity towards S. aureus and were efficient at eliminating the bacteria and counteracting their inflammatory and cytotoxic effects, alone and in combination with low concentrations of gentamicin. We propose that PLNC8 αβ may be developed to combat infections caused by Staphylococcus spp.
Highlights
Staphylococcus aureus (S. aureus) is considered to be one of the most common skin-colonizing bacteria as well as a normal commensal found in the n asopharynx[1]
Bacteriocins are antimicrobial peptides secreted by different types of bacteria and have in recent years emerged as interesting alternatives to conventional antibiotics
In order to further elucidate the antibacterial effects of PLNC8 αβ and lay a foundation for a possible future clinical application, the aim of this study was to characterize the effects of PLNC8 αβ on cell signalling and inflammatory responses of human keratinocytes infected with S. aureus
Summary
Staphylococcus aureus (S. aureus) is considered to be one of the most common skin-colonizing bacteria as well as a normal commensal found in the n asopharynx[1]. Keratinocytes are the major cell type in the skin and are responsible for the initiation and orchestration of early cutaneous immune r esponses[4,5] These cells express different pattern recognition receptors (PRRs) that sense pathogen-associated molecular patterns (PAMPs) of invading pathogens. Activation of these receptors induces signalling pathways, such as nuclear factor κB (NFκB) and mitogen-activated protein kinase (MAPK), resulting in the transcription of proinflammatory genes, for instance those encoding TNF, IL-6 and CXCL85 These cytokines are found to influence immune responses by affecting the migration and proliferation of inflammatory cells. Since it is considered to be more difficult for bacteria to develop resistance against a mechanism involving membrane disruption, plantaricins (Pln) have gained more interest to be developed as alternatives/adjuvants to antibiotic therapy against bacterial infections
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