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This spread is exacerbated by the 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\n              <jats:italic>Desemzia incerta<\/jats:italic>\n              , which we found to exert antimicrobial activity through a secreted product and exhibited colonization resistance against MRSA in an\n              <jats:italic>in vivo<\/jats:italic>\n              murine skin model. Using parallel genomic and biochemical investigation, we discovered that\n              <jats:italic>D. incerta<\/jats:italic>\n              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\n              <jats:italic>D. incerta<\/jats:italic>\n              and MRSA cocultures, we found that exposure to\n              <jats:italic>D. incerta<\/jats:italic>\n              leads to decreased MRSA biofilm production. These results emphasize the value of exploring microbial communities across a spectrum of hosts, which can lead to novel therapeutic agents as well as an increased understanding of microbial competition.\n            <\/jats:p>\n            <jats:sec>\n              <jats:title>IMPORTANCE<\/jats:title>\n              <jats:p>\n                Methicillin-resistant\n                <jats:italic>Staphylococcus aureus<\/jats:italic>\n                (MRSA) causes a 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 the colonization resistance of\n                <jats:italic>S. aureus<\/jats:italic>\n                by bacterial inhibitors previously identified from a porcine skin model. We identify a pig skin commensal,\n                <jats:italic>Desemzia incerta<\/jats:italic>\n                , 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\n                <jats:italic>D. incerta<\/jats:italic>\n                and\n                <jats:italic>S. aureus<\/jats:italic>\n                . We identify 24 candidate antimicrobial proteins secreted by\n                <jats:italic>D. incerta<\/jats:italic>\n                that could be responsible for its antimicrobial activity. We also find that exposure to\n                <jats:italic>D. incerta<\/jats:italic>\n                leads to decreased\n                <jats:italic>S. aureus<\/jats:italic>\n                biofilm formation. These findings show that the livestock transmission of MRSA can be exploited to uncover novel mechanisms of MRSA colonization resistance.\n              <\/jats:p>\n            <\/jats:sec>\n          <\/jats:sec>","DOI":"10.1128\/msphere.00636-23","type":"journal-article","created":{"date-parts":[[2024,2,28]],"date-time":"2024-02-28T14:01:47Z","timestamp":1709128907000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":3,"title":["An exploration of mechanisms underlying\n            <i>Desemzia incerta<\/i>\n            colonization resistance to methicillin-resistant\n            <i>Staphylococcus aureus<\/i>\n            on the skin"],"prefix":"10.1128","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3877-3626","authenticated-orcid":true,"given":"Monica","family":"Wei","sequence":"first","affiliation":[{"name":"Department of Dermatology and Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon A. B.","family":"Knight","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hossein","family":"Fazelinia","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital of Philadelphia, Proteomics Core Facility, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynn","family":"Spruce","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital of Philadelphia, Proteomics Core Facility, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Roof","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital of Philadelphia, Proteomics Core Facility, Philadelphia, Pennsylvania, 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