2349. Elucidating the Pathogenesis of Staphylococcus aureus During Hyperglycemic Osteomyelitis

Abstract

Background Staphylococcus aureus is a leading cause of antibiotic-resistant bacterial infections and can infect nearly every organ of the human body. One common manifestation of S. aureus disease is invasive bone infection, or osteomyelitis. Osteomyelitis is one of the most difficult to treat infections, often necessitating prolonged antibiotic treatment and surgical interventions. Hyperglycemia, or elevated blood glucose concentration, increases the risk for developing osteomyelitis. We hypothesized that S. aureus adapts specifically to the altered host environment during hyperglycemic osteomyelitis, thereby contributing to the increased infection severity. Methods To model hyperglycemic osteomyelitis, we treated mice with streptozotocin prior to infection with S. aureus in a post-traumatic osteomyelitis model. We analyzed bacterial burdens in homogenized tissues and bone parameters with microcomputed tomography. To identify changes in the spatial molecular architecture of infected, hyperglycemic femurs, we utilized imaging mass spectrometry. Finally, to obtain a comprehensive understanding of S. aureus metabolic and virulence changes and identify genes essential for staphylococcal growth in vivo in hyperglycemic mice, we performed a transposon sequencing experiment. Results We discovered that hyperglycemic mice sustained increased bacterial burdens within infected femurs and greater dissemination to other organs. We also found that hyperglycemic infected mice experienced increased rates of bone destruction and loss of trabecular bone volume, suggesting that hyperglycemia exacerbates infection-associated bone loss. Finally, we identified 71 genes as uniquely essential for S. aureus growth during hyperglycemic infection compared to euglycemic infection. Conclusion Hyperglycemia results in increased osteomyelitis infection severity. Multiple S. aureus genes involved in metabolism with roles in bacterial fitness in acidic environments were uniquely essential for bacterial fitness during comorbid infection. By identifying genes contributing to S. aureus survival during hyperglycemic osteomyelitis, we have the potential to inform targeted therapeutic development for treatment of exacerbated infections in patients with comorbid hyperglycemia. Disclosures All Authors: No reported disclosures.