Abstract
The successful treatment of bacterial infections is the achievement of a synergy between the host’s immune defences and antibiotics. Here, we examined whether fosfomycin (FOM) could improve the bactericidal effect of phagocytes, and investigated the potential mechanisms. FOM enhanced the phagocytosis and extra- or intracellular killing of S. aureus by phagocytes. And FOM enhanced the extracellular killing of S. aureus in macrophage (MФ) and in neutrophils mediated by extracellular traps (ETs). ET production was related to NADPH oxidase-dependent reactive oxygen species (ROS). Additionally, FOM increased the intracellular killing of S. aureus in phagocytes, which was mediated by ROS through the oxidative burst process. Our results also showed that FOM alone induced S. aureus producing hydroxyl radicals in order to kill the bacterial cells in vitro. In a mouse peritonitis model, FOM treatment increased the bactericidal extra- and intracellular activity in vivo, and FOM strengthened ROS and ET production from peritoneal lavage fluid ex vivo. An IVIS imaging system assay further verified the observed in vivo bactericidal effect of the FOM treatment. This work may provide a deeper understanding of the role of the host’s immune defences and antibiotic interactions in microbial infections.
Highlights
Biofilm MIBC minimum biofilm bactericidal concentration (MBBC) activity of macrophages (MФ) and human neutrophils against S. aureus; the concrete molecular mechanisms of the synergistic killing bacteria between FOM and phagocytes have not been reported
The total damage percentage that was caused by phagocytes to S. aureus, resuspended biofilm (RBF), or PLK cells were detected with an XTT (2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]2H-tetrazolium-5-carboxanilide) assay at 37 °C for 22 h (Table 2)
These results showed that RBF cells have a strong anti-phagocytic ability against phagocytes compared with PLK cells, and further, that this ability was related to the E:T ratio
Summary
Biofilm MIBC MBBC activity of macrophages (MФ) and human neutrophils against S. aureus; the concrete molecular mechanisms of the synergistic killing bacteria between FOM and phagocytes have not been reported. In addition to active phagocytosis and intracellular killing by ROS, extracellular trap (ET) formation by neutrophils and MФ cells, which is a novel cell death pathway called ETosis, provides an extracellular site for microbial killing in the innate immune defense[21]. To address whether the interactions between FOM and phagocytes against S. aureus are related to the aspects mentioned above, we determined the characteristics and possible mechanisms of their synergistic effects in vitro and in vivo, including ET formation and ROS production
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