Activation of the Pseudomonas aeruginosa Glycerol Regulon Promotes Antibiotic Persistence and Modulates Virulence Phenotypes

Abstract

Chronic infections with Pseudomonas aeruginosa are a major contributor of lung decline in persons with cystic fibrosis (pwCF). P. aeruginosa establishes life-long infections in the CF airway by utilizing various adaptation strategies to persist, including altering the expression of metabolic genes to acquire nutrients that are abundant in the CF airway. Glycerol, which is readily available in the airway, is imported and metabolized by genes in the glp regulon, which is under the control of the GlpR repressor. Previously, it has been shown that the loss of GlpR results in increased biofilm development in a CF-adapted isolate of P. aeruginosa compared to a wound isolate. Based on the increased biofilm phenotype previously observed and because biofilms are associated with increased antibiotic tolerance, we questioned whether GlpR plays a role in mediating antibiotic resistance of P. aeruginosa. In this report, we show that loss of GlpR increases tobramycin resistance of a CF-adapted isolate in synthetic sputum and in airway epithelial cell and Drosophila melanogaster colonization models. Further, transcriptomics analysis revealed that CF-adapted mutants of glpR overexpresses genes involved in multidrug tolerance and chronic infection phenotypes such as alginate. In summary, our study illustrates that activation of the glycerol (glp) regulon may promote P. aeruginosa persistence in the CF airway.