Solithromycin mitigates Prevotella intermedia-induced methicillin-resistant Staphylococcus aureus ventilator-associated pneumonia by enhancing alveolar macrophage function.

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.