An exploration of mechanisms underlying Desemzia incerta colonization resistance to methicillin-resistant Staphylococcus aureus on the skin

Wei, M.; Knight, S. A. B.; Fazelinia, H.; Spruce, L.; Roof, J.; Chu, E. W.; Walsh, J.; Flowers, L.; Kim, D. Y.; Zhu, J.; Grice, E. A.

doi:10.1101/2023.10.11.561853

bioRxiv · 10.1101/2023.10.11.561853

An exploration of mechanisms underlying Desemzia incerta colonization resistance to methicillin-resistant Staphylococcus aureus on the skin

Wei, M.·Knight, S. A. B.·Fazelinia, H.·Spruce, L.·Roof, J.·Chu, E. W.·Walsh, J.·Flowers, L.·Kim, D. Y.·Zhu, J.·Grice, E. A.

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Abstract

Colonization of human skin and nares by methicillin-resistant Staphylococcus aureus (MRSA) leads to community spread of MRSA. This spread is exacerbated by transfer of MRSA between humans and livestock, particularly swine. Here we capitalized on the shared features between human and porcine skin, including shared MRSA colonization, to study novel bacterial mediators of MRSA colonization resistance. We focused on the poorly studied bacterial species Desemzia incerta, which we found to exert antimicrobial activity through a secreted product and exhibited colonization resistance against MRSA in an in vivo murine skin model. Using parallel genomic and biochemical investigation, we discovered that D. incerta secretes an antimicrobial protein. Sequential protein purification and proteomics analysis identified 24 candidate inhibitory proteins, including a promising peptidoglycan hydrolase candidate. Aided by transcriptional analysis of D. incerta and MRSA cocultures, we found that exposure to D. incerta leads to decreased MRSA biofilm production. These results emphasize the value in exploring microbial communities across a spectrum of hosts, which can lead to novel therapeutic agents as well as increased understanding of microbial competition. IMPORTANCEMethicillin-resistant Staphylococcus aureus causes significant healthcare burden and can be spread to the human population via livestock transmission. Members of the skin microbiome can prevent MRSA colonization via a poorly-understood phenomenon known as colonization resistance. Here, we studied colonization resistance of S. aureus by bacterial inhibitors previously identified from a porcine skin model. We identify a pig skin commensal, Desemzia incerta, that reduced MRSA colonization in a murine model. We employ a combination of genomic, proteomic, and transcriptomic analyses to explore the mechanisms of inhibition between D. incerta and S. aureus. We identify 24 candidate antimicrobial proteins secreted by D. incerta that could be responsible for its antimicrobial activity. We also find that exposure to D. incerta leads to decreased S. aureus biofilm formation. These findings show that the livestock transmission of MRSA can be exploited to uncover novel mechanisms of MRSA colonization resistance.

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Wei, M., Knight, S. A. B., Fazelinia, H., Spruce, L., Roof, J., Chu, E. W., Walsh, J., Flowers, L., Kim, D. Y., Zhu, J., Grice, E. A.. 2023-10-13. An exploration of mechanisms underlying Desemzia incerta colonization resistance to methicillin-resistant Staphylococcus aureus on the skin. https://doi.org/10.1101/2023.10.11.561853

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