Tobramycin is a suppressor of premature termination codons

Abstract

Premature translation terminations (PTCs) constitute the molecular basis of many genetic diseases, including cystic fibrosis, as they lead to the synthesis of truncated non-functional or partially functional protein. Suppression of translation terminations at PTCs (read-through) has been developed as a therapeutic strategy to restore full-length protein in several genetic diseases. Phenotypic consequences of PTCs can be exacerbated by the nonsense-mediated mRNA decay (NMD) pathway that detects and degrades mRNA containing PTC. Modulation of NMD, therefore, is also of interest as a potential target for the suppression therapy. Tobramycin is an aminoglycoside antibiotic, normally used to treat Pseudomonas aeruginosa pulmonary infection in CF patients. In the present study, by using yeast as a genetic system, we have examined the ability of Tobramycin to suppress PTCs as a function of the presence or absence of NMD. Results demonstrate that Tobramycin exhibits read-through ability on PTCs and preferentially in absence of NMD.

Keywords: Aminoglycoside antibiotics; CF; CFTR; Cystic Fibrosis Transmembrane Conductance Regulator; Cystic fibrosis; NMD; PTCs; RLUs; Read-through; SD; Tobramycin; Yeast; cystic fibrosis; nonsense-mediated mRNA decay; premature termination codons; relative light units; standard deviation.