| Summary: | Staphylococcus aureus is one of the primary causative agents of skin and wound infections. As bacterial adherence is essential for infection, blocking this step can reduce invasion of host tissues by pathogens. An anti-adhesion therapy, based on a host membrane protein family, the tetraspanins, has been developed that can inhibit the adhesion of S. aureus to human cells. In Chapter 3, we show that peptides based on the EC2 domain of tetraspanins reduce the adherence of various strains of Staphylococcus aureus to host cells, and that the efficacy of these peptides correlates roughly with the expression levels of CD9 on each cell. We also show that one of these peptides, 800, reduces the quantity of viable adhered bacteria in a 3D model of a Staphylococcus aureus wound infection of human skin. Chapter 4 measures the expression levels of various tetraspanins on cells found in the skin by microscopy and flow cytometry, and explores some of the potential ways that interfering with tetraspanins using this peptide therapy could interfere with normal host function, such as cytokine production, wound healing and cell metabolism. No major effects are seen with the peptides, other than a small negative effect of peptide 800 on migration, which was not observed in the skin model measuring epidermal migration. Chapter 5 then looks at 2 ways that therapies could be improved for clinical use: combination therapy and drug delivery. Combining peptide 800 with flucloxacillin, an antibiotic only effective against MSSA, increased its efficacy in a cell line model, however, the opposite occurred in the 3D human skin model. Combining the peptide into nanoparticles using Nanocin™ increased the IC50 and t1/2 of the peptide, however in the skin model anti-adhesive effects were lost.
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