Antivirulence activity of skin microbiome-derived small molecules against Staphylococcus

University Of Kansas Lawrence, Lawrence KS

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Abstract

The human microbiome is composed of trillions of microorganisms that colonize our bodies. These microbes have proved essential to host health through several pathways, including protection against infections. There is a significant gap of knowledge in the field about how the skin microbiome and their metabolites play a role in protection against skin infections. The skin is constantly exposed to the environment and, consequently, to various microbes. Our research group is interested in the role of skin commensals and the molecules they produce on the successful establishment of other commensals and protection against bacterial pathogens. Staphylococcus aureus is a major human pathogen that is often involved in skin and chronic wound infections. S. aureus is also considered of high priority of the development of new therapeutics and strategies due to their increased antimicrobial resistance. Our published data revealed that one major skin commensal, Staphylococcus epidermidis, secretes molecules that affect biofilm formation and dispersal by S. aureus without affecting their growth. We showed that these molecules greatly affect gene expression in S. aureus biofilms, which included other important virulence factors. Furthermore, our preliminary data obtained during the pilot project revealed that adhesion and invasion of epithelial cells is inhibited when S. aureus is grown in the presence of S. epidermidis molecules. Preliminary characterization of the molecule active against S. aureus biofilm formation indicated that the bioactive compound is a highly polar small molecule, resistant to heat and protease treatments. Building up from these data, we hypothesized that S. epidermidis produces molecules that impact S. aureus virulence gene expression, affecting their ability to cause infections. The aims for this project are focused on determining the impact of S. epidermidis-secreted molecules on skin pathogens virulence by evaluating their effect on pathogen adhesion and invasion of keratinocytes, as well as their cytokine production in response to infection. We also aim to determine the impact of the molecules on pathogen gene expression and discover which genes are involved on the phenotype. Finally, we aim to evaluate the therapeutic potential of S. epidermidis-derived bioactive molecule using mouse models of skin infection. The skin microbiome and its chemical repertoire is an understudied field despite being our first line of defense to the external environment. Results obtained in this project will advance our understanding of the chemical ecology of the skin microbiome and the mechanisms involved in their protection against pathogens, potentially leading to new therapeutic strategies.