Designer aminoglycosides prevent cochlear hair cell loss and hearing loss
Markus E. Huth, … , Alan G. Cheng, Anthony J. Ricci
Markus E. Huth, … , Alan G. Cheng, Anthony J. Ricci
Published February 2, 2015; First published January 2, 2015
Citation Information: J Clin Invest. 2015;125(2):583-592. https://doi.org/10.1172/JCI77424.
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Research Article Otology

Designer aminoglycosides prevent cochlear hair cell loss and hearing loss

Abstract

Bacterial infections represent a rapidly growing challenge to human health. Aminoglycosides are widely used broad-spectrum antibiotics, but they inflict permanent hearing loss in up to ~50% of patients by causing selective sensory hair cell loss. Here, we hypothesized that reducing aminoglycoside entry into hair cells via mechanotransducer channels would reduce ototoxicity, and therefore we synthesized 9 aminoglycosides with modifications based on biophysical properties of the hair cell mechanotransducer channel and interactions between aminoglycosides and the bacterial ribosome. Compared with the parent aminoglycoside sisomicin, all 9 derivatives displayed no or reduced ototoxicity, with the lead compound N1MS 17 times less ototoxic and with reduced penetration of hair cell mechanotransducer channels in rat cochlear cultures. Both N1MS and sisomicin suppressed growth of E. coli and K. pneumoniae, with N1MS exhibiting superior activity against extended spectrum β lactamase producers, despite diminished activity against P. aeruginosa and S. aureus. Moreover, systemic sisomicin treatment of mice resulted in 75% to 85% hair cell loss and profound hearing loss, whereas N1MS treatment preserved both hair cells and hearing. Finally, in mice with E. coli–infected bladders, systemic N1MS treatment eliminated bacteria from urinary tract tissues and serially collected urine samples, without compromising auditory and kidney functions. Together, our findings establish N1MS as a nonototoxic aminoglycoside and support targeted modification as a promising approach to generating nonototoxic antibiotics.

Authors

Markus E. Huth, Kyu-Hee Han, Kayvon Sotoudeh, Yi-Ju Hsieh, Thomas Effertz, Andrew A. Vu, Sarah Verhoeven, Michael H. Hsieh, Robert Greenhouse, Alan G. Cheng, Anthony J. Ricci

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Figure 6

Modified aminoglycoside prevents sensory cell loss in vivo.

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Modified aminoglycoside prevents sensory cell loss in vivo. (A) Whole-mo...
(A) Whole-mount preparation showing myosin VIIa–positive hair cells in the cochlear basal turn. Three rows of outer hair cells and a single row of inner hair cells are present in saline-treated animals. (B) Sisomicin treatment caused outer hair cell loss. (C) Hair cells are preserved in N1MS-treated animals. (D) Quantification of myosin VIIa–positive outer hair cells shows dramatic cell loss (as percentages of saline-treated controls) in a basal-apical gradient after sisomicin treatment, whereas N1MS treatment preserved markedly more hair cells. Treatment with 400 mg/kg N1MS produced hair cell loss. Data are shown as average ± SEM. For D, n = 57 for saline control; n = 9–14 for other groups. Scale bar: 25 μm.