Role of Staphylococcus aureus Formate Metabolism during Prosthetic Joint Infection.

Biofilms are bacterial communities characterized by antibiotic tolerance. Staphylococcus aureus is a leading cause of biofilm infections on medical devices, including prosthetic joints, which represent a significant health care burden. The major leukocyte infiltrate associated with S. aureus prosthetic joint infection (PJI) is granulocytic myeloid-derived suppressor cells (G-MDSCs), which produce IL-10 to promote biofilm persistence by inhibiting monocyte and macrophage proinflammatory activity. To determine how S. aureus biofilm responds to G-MDSCs and macrophages, biofilms were cocultured with either leukocyte population followed by RNA sequencing. Several genes involved in fermentative pathways were significantly upregulated in S. aureus biofilm following G-MDSC coculture, including formate acetyltransferase ( pflB ), which catalyzes the conversion of pyruvate and coenzyme-A into formate and acetyl-CoA. A S. aureus pflB mutant (Δ pflB ) did not exhibit growth defects in vitro . However, Δ pflB formed taller and more diffuse biofilm compared to the wild-type strain as revealed by confocal microscopy. In a mouse model of PJI, the bacterial burden was significantly reduced with Δ pflB during later stages of infection, which coincided with decreased G-MDSC influx and increased neutrophil recruitment, and Δ pflB was more susceptible to macrophage killing. Although formate was significantly reduced in the soft tissue surrounding the joint of Δ pflB -infected mice levels were increased in the femur, suggesting that host-derived formate may also influence bacterial survival. This was supported by the finding that a Δ pflB Δ fdh strain defective in formate production and catabolism displayed a similar phenotype to Δ pflB . These results revealed that S. aureus formate metabolism is important for promoting biofilm persistence.