A Newly Identified Role of the Tectorial Membrane in Aminoglycoside Ototoxicity

Abstract

Aminoglycoside (AG) antibiotic safety is limited by ototoxicity, the mitigation of which is vital considering bacterial resistance mediated erosion of our antibiotic arsenal. Previously, we observed tectorial membrane (TM) sequestration of Ca2+. We hypothesized that the TM sequesters other cations, including the AG gentamicin. We proposed to test the effect of TM genetic ablation on ototoxicity and TM-AG sequestration. After intraperitoneal AG-furosemide, TM-lacking Tecta{Delta}ENT/{Delta}ENT mice showed limited outer hair cell loss, unlike wildtype littermates. Spectroscopy measurements of gentamicin-Texas red (GTTR) were made in isolated wildtype and TectaY1870C TMs and guinea pig cochleae following direct or intraperitoneal GTTR administration. TM-GTTR sequestration was observed in all cases, while negatively correlated with TectaY1870C zygosity. In summary, we discovered a novel TM component in the AG ototoxicity pathway. Intact TM structure is necessary for sequestration, and the TM modulates AG ototoxicity. TM-GTTR sequestration following systemic injection indicates that this phenomenon occurs during AG therapy. Single sentence summaryOtotoxic aminoglycosides collect inside the acellular tectorial membrane of the inner ear, likely due to electrostatic interactions, and the structural status of that membrane modulates the toxic effect of those aminoglycosides on sensory hair cells.