Frontiers in cellular and infection microbiology · 2026
Solithromycin mitigates Prevotella intermedia-induced methicillin-resistant Staphylococcus aureus ventilator-associated pneumonia by enhancing alveolar macrophage function.
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Fukushima Koki, Iwanaga Naoki, Ashizawa Nobuyuki, Takeda Kazuaki, Hirayama Tatsuro, Yoshida Masataka, Ide Shotaro, Takazono Takahiro, Kosai Kosuke, Sakamoto Noriho, Naito Mariko, Yanagihara Katsunori, Mukae Hiroshi
Аннотация
BACKGROUND: Ventilator-associated pneumonia (VAP) is a fatal intensive care infection. VAP caused by methicillin-resistant Staphylococcus aureus (MRSA) can be exacerbated by Prevotella intermedia culture supernatant (P. int. sup.). Solithromycin (SOL), a fourth-generation macrolide, inhibits bacterial protein synthesis and modulates immunity; however, its effects on exacerbation of MRSA-VAP by P. int. sup. remain unclear. This study examined whether SOL inhibits bacterial protein synthesis by binding to the 50S ribosomal subunits in P. int. sup. and subsequently reduces the worsening of MRSA-VAP caused by P. int. sup.
METHODS: BALB/cCrSlc mice received MRSA and P. int. sup. with or without sub-minimum inhibitory concentrations of SOL (P. int. sup. (SOL)) or clarithromycin (CAM; P. int. sup. (CAM)). Outcomes included survival rates, lung MRSA burden, and transcriptomics (reverse transcription polymerase chain reaction, bulk RNA sequencing [RNA-seq]). In vitro, bone marrow-derived alveolar macrophage-like cells (AMLCs) from C57BL/6J mice were infected with MRSA ± SOL; bactericidal activity and mRNA expression were measured.
RESULTS: P. int. sup. increased mortality, bacterial load, and neutrophilic infiltration; however, P. int. sup. (SOL) significantly improved survival rate (100%, n = 8, ****P < 0.0001), reduced MRSA burden (n = 10-11, **P < 0.01), and enhanced macrophage recruitment (n = 7-8, ****P < 0.001). P. int. sup. downregulated Ccr2 expression (n = 7-8, ***P < 0.001). RNA-seq analysis revealed P. int. sup. (SOL) upregulated macrophage phagocytosis and bactericidal pathways. SOL-pretreated AMLCs infected with MRSA exhibited reduced bacterial burden (n = 8, *P < 0.05 vs control, **P < 0.01 vs CAM-pretreated AMLCs) and upregulated Tnf-α expression (n = 7-8, *P < 0.05 vs control).
CONCLUSION: 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 P. int. sup.
METHODS: BALB/cCrSlc mice received MRSA and P. int. sup. with or without sub-minimum inhibitory concentrations of SOL (P. int. sup. (SOL)) or clarithromycin (CAM; P. int. sup. (CAM)). Outcomes included survival rates, lung MRSA burden, and transcriptomics (reverse transcription polymerase chain reaction, bulk RNA sequencing [RNA-seq]). In vitro, bone marrow-derived alveolar macrophage-like cells (AMLCs) from C57BL/6J mice were infected with MRSA ± SOL; bactericidal activity and mRNA expression were measured.
RESULTS: P. int. sup. increased mortality, bacterial load, and neutrophilic infiltration; however, P. int. sup. (SOL) significantly improved survival rate (100%, n = 8, ****P < 0.0001), reduced MRSA burden (n = 10-11, **P < 0.01), and enhanced macrophage recruitment (n = 7-8, ****P < 0.001). P. int. sup. downregulated Ccr2 expression (n = 7-8, ***P < 0.001). RNA-seq analysis revealed P. int. sup. (SOL) upregulated macrophage phagocytosis and bactericidal pathways. SOL-pretreated AMLCs infected with MRSA exhibited reduced bacterial burden (n = 8, *P < 0.05 vs control, **P < 0.01 vs CAM-pretreated AMLCs) and upregulated Tnf-α expression (n = 7-8, *P < 0.05 vs control).
CONCLUSION: 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 P. int. sup.