Elevated glucose increases <i>Staphylococcus aureus</i> antibiotic resistance in a cystic fibrosis airway epithelial cell infection model

In a healthy lung, the airway epithelium regulates glucose transport to maintain low glucose concentrations in the airway surface liquid (ASL). However, hyperglycemia and chronic lung diseases, such as cystic fibrosis (CF), can result in increased glucose in bronchial aspirates. People with CF are also at increased risk of lung infections caused by bacterial pathogens, including methicillin-resistant <i>Staphylococcus aureus</i>. Yet, it is not known how increased airway glucose availability affects bacteria in chronic CF lung infections or impacts treatment outcomes. To model the CF airways, we cultured immortalized CF (CFBE41o-) and non-CF (16HBE) human bronchial epithelial cells at the air-liquid interface (ALI). Glucose concentrations in the basolateral media were maintained at 5.5 or 12.5 mM to mimic a normal and hyperglycemic milieu, respectively. We found that glucose concentrations in the ASL of ALI cultures maintained in normal or high glucose mimicked levels measured in breath condensate assays from people with CF and hyperglycemia. Additionally, we found hyperglycemia increased <i>S. aureus</i> aggregation and antibiotic resistance during infection of cells maintained in high glucose compared to normal glucose conditions. Heightened antibiotic resistance was not observed during <i>in vitro</i> growth with elevated glucose. Limiting glucose with 2-deoxyglucose both decreased aggregation and reduced antibiotic resistance back to levels comparable to non-hyperglycemic conditions. These data indicate that hyperglycemia alters <i>S. aureus</i> growth during infection and may reduce efficacy of antibiotic treatment. Glucose restriction is a potential option that could be explored to limit bacterial growth and improve treatment outcomes in chronic airway infections.