Cefiderocol has immunoregulative effects in LPS-induced vitro experimental model via inhibiting inflammation and ferroptosis

• Published in: International journal of antimicrobial agents 2024-12, Vol.64 (6), p.107374, Article 107374
• Main Authors: Ju, Mohan, Hao, Min, Lin, Dongfang, Liu, Shuang
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents - pharmacology; Cefiderocol; Cephalosporins - pharmacology; Cephalosporins - therapeutic use; Cytokines - metabolism; Ferroptosis; Ferroptosis - drug effects; Glutathione - metabolism; Inflammation; Inflammation - drug therapy; Lipopolysaccharide; Lipopolysaccharides - pharmacology; Macrophage; Macrophages - drug effects; Macrophages - immunology; Malondialdehyde - metabolism; Mice; RAW 264.7 Cells; Reactive Oxygen Species - metabolism
• ISSN: 0924-8579; 1872-7913; 1872-7913
• DOI: 10.1016/j.ijantimicag.2024.107374

Cefiderocol is a new catecholamine-containing siderophore cephalosporin. It, however, remains unclear how cefiderocol modulates the immune response of the host. This study elucidated whether cefiderocol exerts immunoprotective effects in an in vitro experimental model induced with lipopolysaccharide (LPS). Mouse macrophage RAW 264.7 cells were exposed to LPS (100 ng/mL) or LPS + cefiderocol (40 mg/L) to assess the immunomodulatory effect of cefiderocol in vitro. ELISA was performed on cell culture supernatants to estimate cytokine levels. Ferroptosis level was also quantified by detecting intracellular reactive oxygen species and iron levels through flow cytometry analysis. Malondialdehyde and glutathione (GSH) levels were estimated by ELISA. We conducted western blotting assay for evaluating key ferroptosis pathway proteins. Cefiderocol alleviated LPS-induced inflammation by reducing IL-6, TNF-α, and IL-1β production levels and enhancing the IL-10 production level. Further analysis to determine the underlying mechanism revealed that cefiderocol inhibited ferroptosis; this was confirmed by reduced reactive oxygen species, malondialdehyde, and Fe2+ ion levels; increased GSH levels; upregulated expression of solute carrier family 7 member 11, GSH peroxidase 4, nuclear factor erythroid 2-related factor 2, and ferroptosis suppressor protein 1; and downregulated expression of acyl-CoA synthetase long-chain family member 4. Cefiderocol may play a key role in reducing inflammation by decreasing inflammatory cytokine release and suppressing ferroptosis. [Display omitted]