{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:11:40Z","timestamp":1787026300403,"version":"build-2736575974"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T00:00:00Z","timestamp":1770595200000},"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:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Ventilator-associated pneumonia (VAP) is a fatal intensive care infection. VAP caused by methicillin-resistant\n                      <jats:italic>Staphylococcus aureus<\/jats:italic>\n                      (MRSA) can be exacerbated by\n                      <jats:italic>Prevotella intermedia<\/jats:italic>\n                      culture supernatant (\n                      <jats:italic>P. int.<\/jats:italic>\n                      sup.). Solithromycin (SOL), a fourth-generation macrolide, inhibits bacterial protein synthesis and modulates immunity; however, its effects on exacerbation of MRSA-VAP by\n                      <jats:italic>P. int<\/jats:italic>\n                      . sup. remain unclear. This study examined whether SOL inhibits bacterial protein synthesis by binding to the 50S ribosomal subunits in\n                      <jats:italic>P. int<\/jats:italic>\n                      . sup. and subsequently reduces the worsening of MRSA-VAP caused by\n                      <jats:italic>P. int.<\/jats:italic>\n                      sup.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      BALB\/cCrSlc mice received MRSA and\n                      <jats:italic>P. int.<\/jats:italic>\n                      sup. with or without sub-minimum inhibitory concentrations of SOL (\n                      <jats:italic>P. int<\/jats:italic>\n                      . sup. (SOL)) or clarithromycin (CAM;\n                      <jats:italic>P. int.<\/jats:italic>\n                      sup. (CAM)). Outcomes included survival rates, lung MRSA burden, and transcriptomics (reverse transcription polymerase chain reaction, bulk RNA sequencing [RNA-seq]).\n                      <jats:italic>In vitro<\/jats:italic>\n                      , bone marrow-derived alveolar macrophage-like cells (AMLCs) from C57BL\/6J mice were infected with MRSA \u00b1 SOL; bactericidal activity and mRNA expression were measured.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>P. int<\/jats:italic>\n                      . sup. increased mortality, bacterial load, and neutrophilic infiltration; however,\n                      <jats:italic>P. int<\/jats:italic>\n                      . sup. (SOL) significantly improved survival rate (100%,\n                      <jats:italic>n<\/jats:italic>\n                      = 8, ****P &amp;lt; 0.0001), reduced MRSA burden (\n                      <jats:italic>n<\/jats:italic>\n                      = 10\u201311, **P &amp;lt; 0.01), and enhanced macrophage recruitment (\n                      <jats:italic>n<\/jats:italic>\n                      = 7\u20138, ****P &amp;lt; 0.001).\n                      <jats:italic>P. int.<\/jats:italic>\n                      sup. downregulated\n                      <jats:italic>Ccr2<\/jats:italic>\n                      expression (\n                      <jats:italic>n<\/jats:italic>\n                      = 7\u20138, ***P &amp;lt; 0.001). RNA-seq analysis revealed\n                      <jats:italic>P. int<\/jats:italic>\n                      . sup. (SOL) upregulated macrophage phagocytosis and bactericidal pathways. SOL-pretreated AMLCs infected with MRSA exhibited reduced bacterial burden (\n                      <jats:italic>n<\/jats:italic>\n                      = 8, *P &amp;lt; 0.05 vs control, **P &amp;lt; 0.01 vs CAM-pretreated AMLCs) and upregulated\n                      <jats:italic>Tnf-\u03b1<\/jats:italic>\n                      expression (\n                      <jats:italic>n<\/jats:italic>\n                      = 7\u20138, *P &amp;lt; 0.05 vs control).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      SOL protects by activating alveolar macrophages and promoting TNF-related responses, suggesting a novel immunomodulatory role for SOL in host defense against exacerbation of MRSA-VAP by\n                      <jats:italic>P. int.<\/jats:italic>\n                      sup.\n                    <\/jats:p>\n                  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