Solithromycin mitigates-induced methicillin-resistantventilator-associated pneumonia by enhancing alveolar macrophage function.

Abstract

BACKGROUND: Ventilator-associated pneumonia (VAP) is a fatal intensive care infection. VAP caused by methicillin-resistant(MRSA) can be exacerbated byculture supernatant (sup.). Solithromycin (SOL), a fourth-generation macrolide, inhibits bacterial protein synthesis and modulates immunity; however, its effects on exacerbation of MRSA-VAP by. sup. remain unclear. This study examined whether SOL inhibits bacterial protein synthesis by binding to the 50S ribosomal subunits in. sup. and subsequently reduces the worsening of MRSA-VAP caused bysup. METHODS: BALB/cCrSlc mice received MRSA andsup. with or without sub-minimum inhibitory concentrations of SOL (. sup. (SOL)) or clarithromycin (CAM;sup. (CAM)). Outcomes included survival rates, lung MRSA burden, and transcriptomics (reverse transcription polymerase chain reaction, bulk RNA sequencing [RNA-seq])., bone marrow-derived alveolar macrophage-like cells (AMLCs) from C57BL/6J mice were infected with MRSA &#xb1; SOL; bactericidal activity and mRNA expression were measured. RESULTS: . sup. increased mortality, bacterial load, and neutrophilic infiltration; however,. sup. (SOL) significantly improved survival rate (100%,= 8, ****P < 0.0001), reduced MRSA burden (= 10-11, **P < 0.01), and enhanced macrophage recruitment (= 7-8, ****P < 0.001).sup. downregulatedexpression (= 7-8, ***P < 0.001). RNA-seq analysis revealed. sup. (SOL) upregulated macrophage phagocytosis and bactericidal pathways. SOL-pretreated AMLCs infected with MRSA exhibited reduced bacterial burden (= 8, *P < 0.05 vs control, **P < 0.01 vs CAM-pretreated AMLCs) and upregulatedexpression (= 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 bysup.