{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T15:14:08Z","timestamp":1786115648197,"version":"build-2736575974"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>\n                    Intracellular infection by\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    (\n                    <jats:italic>S. aureus<\/jats:italic>\n                    ) is a major driver of persistent osteomyelitis, leading to antibiotic failure and recurrent bone destruction. However, the precise host-pathogen interactions and mechanisms underlying bacterial internalization remain incompletely understood. In this study, we employed an\n                    <jats:italic>in vitro<\/jats:italic>\n                    intracellular infection model using bone marrow mesenchymal stem cells alongside an\n                    <jats:italic>in vivo<\/jats:italic>\n                    murine osteomyelitis model. Integrated multi-omics, structure-guided molecular docking, and mutation analyses revealed that\n                    <jats:italic>S. aureus<\/jats:italic>\n                    promotes the physical recruitment of the host adapter Mprip specifically to the Talin-1 D125 residue. This structural binding triggers the subsequent Talin-1 phosphorylation cascade, which exerts a dual pathological effect: facilitating extensive bacterial internalization and suppressing osteogenic recovery via the PI3K\/AKT pathway. Genetic deletion of Mprip or Talin-1 markedly reduced the bacterial burden and restored osteogenesis. Furthermore, through structure-based virtual screening targeting the binding interface at residue D125, we identified a specific small molecule, UM-164. UM-164 effectively disrupted the Mprip\/Talin-1 interaction and blocked subsequent Talin-1 phosphorylation. By effectively inhibiting bacterial internalization, UM-164 restricted bacteria to the extracellular space, thereby synergizing with systemic gentamicin to reduce the overall bacterial burden and mitigate bone destruction\n                    <jats:italic>in vivo<\/jats:italic>\n                    . In conclusion, the structural binding of Mprip to Talin-1 and the resulting phosphorylation cascade drive\n                    <jats:italic>S. aureus<\/jats:italic>\n                    osteomyelitis through a dual mechanism of bacterial internalization and PI3K\/AKT-mediated osteogenic suppression. UM-164, a small molecule specifically screened to target the Mprip\/Talin-1 D125 interface, presents a potent host-directed strategy to prevent bacterial internalization and potentiate antibiotic efficacy in recalcitrant bone infections.\n                  <\/jats:p>","DOI":"10.3389\/fcimb.2026.1823065","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T04:25:32Z","timestamp":1785990332000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Enhancement of antibiotic therapy in osteomyelitis by inhibiting talin-1-mediated bacterial internalization"],"prefix":"10.3389","volume":"16","author":[{"given":"Yuntao","family":"Li","sequence":"first","affiliation":[{"name":"Department of Orthopedics, Shanghai Key Laboratory of Orthopedic Implant, Shanghai Ninth People\u2019s Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanliang","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Anesthesia, Shanghai Ninth People\u2019s Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hairong","family":"Tao","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Shanghai Key Laboratory of Orthopedic Implant, Shanghai Ninth People\u2019s Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"3421","DOI":"10.1016\/j.molcel.2023.08.029","article-title":"RANK ligand converts the NCoR\/HDAC3 co-repressor to a PGC1\u03b2- and RNA-dependent co-activator of osteoclast gene expression","volume":"83","author":"Abe","year":"2023","journal-title":"Mol. 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