Lower ototoxicity and absence of hidden hearing loss point to gentamicin C1a and apramycin as promising antibiotics for clinical use

• Published in: Scientific Reports Vol. 9; no. 1; p. 2410
• Main Authors: Ishikawa, Masaaki, García-Mateo, Nadia, Čusak, Alen, López-Hernández, Iris, Fernández-Martínez, Marta, Müller, Marcus, Rüttiger, Lukas, Singer, Wibke, Löwenheim, Hubert, Kosec, Gregor, Fujs, Štefan, Martínez-Martínez, Luis, Schimmang, Thomas, Petković, Hrvoje, Knipper, Marlies, Durán-Alonso, M. Beatriz
• Format: Journal Article
• Language: English
• Published: London Springer Science and Business Media LLC 20.02.2019; Nature Publishing Group UK; Nature Publishing Group
• Subjects: 13; 13/106; 13/51; 631/154/1438; 692/308/153; 96; Action potential; Aminoglycoside antibiotics; Aminoglycosides; Aminoglycosides - adverse effects; Aminoglycosides - pharmacology; Animals; Anti-Bacterial Agents; Anti-Bacterial Agents - adverse effects; Anti-Infective Agents; Anti-Infective Agents - adverse effects; Anti-Infective Agents - pharmacology; Antibiotics; Antimicrobial resistance; Apramycin; Cell Line; Cell survival; Clinical isolates; Drug Resistance, Bacterial; Drug Resistance, Bacterial - drug effects; Drug Resistance, Bacterial - genetics; Gentamicin; Gentamicins; Gentamicins - adverse effects; Gentamicins - pharmacology; Gentamicins - therapeutic use; Guinea Pigs; Hair; Hair cells; Hair Cells, Auditory, Inner; Hair Cells, Auditory, Inner - drug effects; Hair Cells, Auditory, Inner - pathology; Hearing Loss; Hearing Loss - chemically induced; Hearing Loss - genetics; Hearing Loss - pathology; Hearing protection; Humanities and Social Sciences; Humans; multidisciplinary; Multidrug resistance; Nebramycin; Nebramycin - adverse effects; Nebramycin - analogs & derivatives; Nebramycin - pharmacology; Neomycin; Neomycin - adverse effects; Neomycin - pharmacology; Ototoxicity; Ototoxicity - metabolism; Ototoxicity - pathology; Paromomycin; Protein Synthesis Inhibitors; Protein Synthesis Inhibitors - adverse effects; Protein Synthesis Inhibitors - pharmacology; Round Window, Ear; Round Window, Ear - drug effects; Round Window, Ear - pathology; Science; Science (multidisciplinary); Synaptic ribbons
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-38634-3

Spread of antimicrobial resistance and shortage of novel antibiotics have led to an urgent need for new antibacterials. Although aminoglycoside antibiotics (AGs) are very potent anti-infectives, their use is largely restricted due to serious side-effects, mainly nephrotoxicity and ototoxicity. We evaluated the ototoxicity of various AGs selected from a larger set of AGs on the basis of their strong antibacterial activities against multidrug-resistant clinical isolates of the ESKAPE panel: gentamicin, gentamicin C1a, apramycin, paromomycin and neomycin. Following local round window application, dose-dependent effects of AGs on outer hair cell survival and compound action potentials showed gentamicin C1a and apramycin as the least toxic. Strikingly, although no changes were observed in compound action potential thresholds and outer hair cell survival following treatment with low concentrations of neomycin, gentamicin and paromomycin, the number of inner hair cell synaptic ribbons and the compound action potential amplitudes were reduced. This indication of hidden hearing loss was not observed with gentamicin C1a or apramycin at such concentrations. These findings identify the inner hair cells as the most vulnerable element to AG treatment, indicating that gentamicin C1a and apramycin are promising bases for the development of clinically useful antibiotics.