Cystic fibrosis (CF) is a life-threatening disease inherited by approximately one in 2,500 American children each year. CF is diagnosed by defects in the cystic transmembrane conductance regulator gene, which causes an over-accumulation of thickened mucus that coats the lungs and acts as an ideal breeding ground for bacterial infections. The main cause of fatality in CF patients is directly related to infection with a deadly bacterial pathogen, Pseudomonas aeruginosa. Antimicrobials are the main treatment focus for CF due to the patient’s vulnerability to infection. The highly adaptive nature of P. aeruginosa, in addition to the intrinsic resistance to many antibiotics exhibited by most Gram-negative bacteria, means that multi-drug resistant strains are increasingly prevalent. This results in eradication of pseudomonal lung infections becoming nearly impossible once the infection becomes chronic. New methods to treat pseudomonal infections by both lowering inflammation within the respiratory tract and eradicating the bacteria responsible for this inflammation are greatly needed to better the quality of life for CF patients. Azithromycin is a macrolide antibiotic currently prescribed to CF patients as an anti-inflammatory agent due to its well-documented ability to lower inflammation in patients with known respiratory diseases. However, P. aeruginosa exhibits intrinsic resistance to macrolide antibiotics, including azithromycin, making this antibiotic ineffective in eradicating infections caused by this bacterium. Herein, we describe a novel approach for combatting pseudomonal infections through the use of nonmicrobicidal bis-2-aminoimidazole (bis-2-AI) adjuvants that suppress azithromycin resistance in a highly resistant strain of P. aeruginosa. Our lead bis-2-AI exhibits a 1024-fold reduction in the minimum inhibitory concentration of azithromycin in vitro and increases survival rates in a Galleria mellonella model of infection, demonstrating the potential dual use of azithromycin not only as an anti-inflammatory agent, but also as an antibiotic for CF treatment regimens.

Using small molecule adjuvants to combat antibiotic resistant bacteria in cystic fibrosis

2019 Spring National Meeting

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