Behavioral dynamics of Staphylococcus aureus and Pseudomonas aeruginosa in diabetic infections: interactions, antibiotic resistance, and host immune response

Diabetes mellitus (DM) is a growing global health crisis associated with increased susceptibility to recurrent bacterial infections stemming from chronic hyperglycemia, immune dysfunction, and increased rates of infection with antibiotic-resistant pathogens. Individuals with DM are susceptible to polymicrobial skin and soft tissue infections, with the pathogens Staphylococcus aureus and Pseudomonas aeruginosa among the most frequently isolated species. Although the interaction dynamics between these bacteria are well characterized in cystic fibrosis pulmonary disease, less is known about how diabetic status shapes their behaviors during co-infection. To address this knowledge gap, this dissertation sought to define how DM-associated complications influenced S. aureus and P. aeruginosa co-infection behaviors, including bacterial growth, persistence, and antibiotic responses.Using a murine indwelling device model, we demonstrate that diabetic conditions support coexistence between S. aureus and P. aeruginosa, a phenotype contingent on intact S. aureus glycolytic metabolism. In vitro, glucose supplementation enabled S. aureus to overcome growth inhibition mediated by P. aeruginosa respiratory toxins; however, these toxins did not account for S. aureus growth suppression during in vivo co-infection. This divergence between in vitro and in vivo results extended to antibiotic resistance outcomes: although P. aeruginosa respiratory toxins prevented S. aureus from acquiring de novo rifampicin resistance under hyperglycemic conditions in vitro, S. aureus readily developed resistance during subcutaneous diabetic co-infection with P. aeruginosa under rifampicin treatment. Collectively, these results indicate that host diabetic status reshapes polymicrobial interactions, underscore the limitations of solely using in vitro systems to model complex host-associated diseases, and expand the relevance of studying S. aureus and P. aeruginosa co-infections to diabetic niches.