Concurrent targeting of glycolysis in bacteria and host cell inflammation in septic arthritis.

Intracellular infiltration of bacteria into host cells complicates medical and surgical treatment of bacterial joint infections. Unlike soft tissue infections, septic arthritis and infection‐associated inflammation destroy cartilage that does not regenerate once damaged. Herein, we show that glycolytic pathways are shared by methicillin‐resistant Staphylococcus aureus (MRSA) proliferation and host inflammatory machinery in septic arthritis. MRSA readily penetrates host cells and induces proinflammatory cascades that persist after conventional antibiotic treatment. The glycolysis‐targeting drug dimethyl fumarate (DMF) showed both bacteriostatic and anti‐inflammatory effects by hindering the proliferation of intracellular MRSA and dampening excessive intraarticular inflammation. Combinatorial treatment with DMF and vancomycin further reduced the proliferation and re‐emergence of intracellular MRSA. Combinatorial adjuvant administration of DMF with antibiotics alleviated clinical symptoms of septic arthritis by suppressing bacterial burden and curbing inflammation to protect cartilage and bone. Our results provide mechanistic insight into the regulation of glycolysis in the context of infection and host inflammation toward development of a novel therapeutic paradigm to ameliorate joint bioburden and destruction in septic arthritis. Synopsis: Septic arthritis has limitations such as intracellular bacteria and inflammatory tissue disruption even after conventional treatment. This study shows evidence of the potential of repurposing of glycolysis targeting DMF in conjunction with a conventional antibiotic to ameliorate septic arthritis. Intraarticular inflammation and glycolysis are induced in the setting of MRSA septic arthritis.Inhibition of glycolysis with DMF normalizes the production of proinflammatory markers within the joint space.DMF inhibits bacterial replication, intracellular bioburden, and biofilm formation via bacteriostatic effects.Administration of DMF adjuvant to systemic antibiotics alleviates the clinical symptoms and pathologic signs of septic arthritis. [ABSTRACT FROM AUTHOR]