Anti-Infectives Restore ORKAMBI^® Rescue of F508del-CFTR Function in Human Bronchial Epithelial Cells Infected with Clinical Strains of <i>P. aeruginosa</i>

• Main Authors: Onofrio Laselva, Tracy A. Stone, Christine E. Bear, Charles M. Deber
• Format: Article
• Language: English
• Published: MDPI AG 2020-02-01
• Series: Biomolecules
• Subjects: cftr; correctors; antimicrobial peptide; tobramycin; infection; anti-inflammatory; <i>pseudomonas aeruginosa</i>; clinical strains; multidrug resistant bacteria
• Online Access: https://www.mdpi.com/2218-273X/10/2/334

Chronic infection and inflammation are the primary causes of declining lung function in Cystic Fibrosis (CF) patients. ORKAMBI^&#174; (Lumacaftor-Ivacaftor) is an approved combination therapy for Cystic Fibrosis (CF) patients bearing the most common mutation, F508del, in the cystic fibrosis conductance regulator (CFTR) protein. It has been previously shown that ORKAMBI^&#174;-mediated rescue of CFTR is reduced by a pre-existing <i>Pseudomonas aeruginosa</i> infection. Here, we show that the infection of F508del-CFTR human bronchial epithelial (HBE) cells with lab strain and four different clinical strains of <i>P. aeruginosa,</i> isolated from the lung sputum of CF patients, decreases CFTR function in a strain-specific manner by 48 to 88%. The treatment of infected cells with antibiotic tobramycin or cationic antimicrobial peptide 6K-F17 was found to decrease clinical strain bacterial growth on HBE cells and restore ORKAMBI^&#174;-mediated rescue of F508del-CFTR function. Further, 6K-F17 was found to downregulate the expression of pro-inflammatory cytokines, interleukin (IL)-8, IL-6, and tumor necrosis factor-&#945; in infected HBE cells. The results provide strong evidence for a combination therapy approach involving CFTR modulators and anti-infectives (i.e., tobramycin and/or 6K-F17) to improve their overall efficacy in CF patients.