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Updated: Feb 26, 2026
Alveolar Macrophage Phagocytosis and Bacteria Clearance in Mice
Published on: March 2, 2019
Solithromycin mitigates Prevotella intermedia-induced methicillin-resistant Staphylococcus aureus
Koki Fukushima1,2, Naoki Iwanaga1,2, Nobuyuki Ashizawa2
1Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
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.
Insights
Solithromycin (SOL) treatment significantly improved survival and reduced bacterial burden in mice with methicillin-resistant Staphylococcus aureus (MRSA) ventilator-associated pneumonia (VAP) exacerbated by Prevotella intermedia. SOL enhances macrophage activity and host defense.
Area of Science:
- Infectious Diseases
- Microbiology
- Immunology
- Pharmacology
Background:
- Ventilator-associated pneumonia (VAP) is a critical care infection with high mortality.
- Methicillin-resistant Staphylococcus aureus (MRSA) VAP can be worsened by Prevotella intermedia culture supernatant (P. int. sup.).
- The efficacy of Solithromycin (SOL), a fourth-generation macrolide, against MRSA-VAP exacerbated by P. int. sup. is not well understood.
Purpose of the Study:
- To investigate if SOL inhibits bacterial protein synthesis by binding to 50S ribosomal subunits in P. int. sup.
- To determine if SOL reduces the exacerbation of MRSA-VAP caused by P. int. sup.
Main Methods:
- Mice models of MRSA-VAP were treated with SOL or clarithromycin (CAM) in combination with P. int. sup.
- Evaluated outcomes included survival rates, lung MRSA burden, and transcriptomic analysis (RNA-seq).
- In vitro studies used alveolar macrophage-like cells (AMLCs) to assess bactericidal activity and mRNA expression.
Main Results:
- SOL treatment significantly improved survival rates (100%) and reduced MRSA burden in mice.
- SOL enhanced macrophage recruitment and upregulated pathways related to phagocytosis and bacterial killing.
- SOL-pretreated AMLCs showed reduced bacterial burden and increased TNF-α expression.
Conclusions:
- Solithromycin demonstrates protective effects against MRSA-VAP exacerbated by P. int. sup.
- SOL activates alveolar macrophages and promotes TNF-related immune responses.
- This suggests a novel immunomodulatory role for SOL in bolstering host defense mechanisms.
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