Background: The increasing emergence of multidrug-resistant Gram-positive bacterial infections necessitates new antibacterial agents with novel mechanisms of action that can be used to treat these infections. Lomitapide has been approved by FDA for years in reducing levels of low-density lipoprotein (LDL) in cases of familial hypercholesterolemia, whereas the antibacterial effect of lomitapide remains elusive. In this study, the inhibitory activities of lomitapide against Gram-positive bacteria were the first time explored. Quantitative proteomics analysis was then applied to investigate the mechanisms of action of lomitapide. Results: The minimum inhibitory concentration (MIC) values of lomitapide against Gram-positive bacteria including both methicillin sensitive and resistant Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Enterococcus faecium, and Streptococcus agalactiae were range 12.5–50 μM. Moreover, lomitapide also inhibited anti-biofilm activity against clinical S. aureus isolates. A total of 106 proteins with > 1.5-fold changes in expression were identified upon 1/2 × MIC lomitapide exposure, including 83 up-regulated proteins and 23 down-regulated proteins. Based on bioinformatics analysis, the expression of cell wall damage response proteins including two-component system VraS/VraR, lipoteichoic acid (LPA) D-alanylnation related proteins D-alanyl carrier protein (dltC) and carrier protein ligase (dltA), methionine sulfoxide reductases (mrsA1 and mrsB) were up-regulated. Moreover, the expression of SaeS and multiple fibrinogen-binding proteins (SAOUHSC_01110, FnBPB, SAOUHSC_02802, SdrC, SdrD) which were involved in the bacterial adhesion and biofilm formation, was inhibited by lomitapide. Furthermore, VraS/VraR deletion mutant (ΔvraSR) showed an enhanced lomitapide sensitivity phenotype. Conclusion: Lomitapide displayed broad antimicrobial activities against Gram-positive bacteria. The antibacterial effect of lomitapide may be caused by cell wall destruction, while the anti-biofilm activity may be related to the inhibition of surface proteins.

Background: Histidine-rich glycoprotein (HRG), a potential prognostic factor in sepsis, lacks clarity regarding its relevance in septic-induced shock, disseminated intravascular coagulation (DIC), and acute respiratory distress syndrome (ARDS) pathogenesis. This study investigated the association between HRG concentrations and these critical conditions. Methods: Blood samples were collected from 53 critically ill patients on days 1, 3, 5, and 7 after ICU admission at the Kyushu University Hospital. Daily clinical and laboratory data were recorded, and patient survival was assessed 28 days after ICU admission. Results: Serum HRG concentrations were significantly reduced on days 3, 5, and 7 in patients with septic shock and DIC but not in those with ARDS. While initial HRG levels on day one were not correlated with survival, nonsurvivors displayed decreased HRG levels, notably on days 3, 5, and 7 post-ICU admissions. The HRG levels remained stable in survivors. A progressive decrease was associated with higher mortality rates, particularly on days 5 and 7. On day 5, an HRG level with a cutoff of 25.5 μg/mL showed a sensitivity of 0.77 and a specificity of 0.75, indicating significantly lower survival rates (log-rank test, P < 0.05). Conclusion: HRG presents a potential intervention for critically ill sepsis patients, providing a novel strategy to enhance outcomes. Further research is needed to explore the therapeutic potential of HRG in sepsis management.