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 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 7

N1MS eradicates urinary tract infection in vivo.

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N1MS eradicates urinary tract infection in vivo. (A) Schematic of E. col...
(A) Schematic of E. coli infection of the mouse urinary tract and treatment with sisomicin or N1MS. The uropathogenic E. coli strain UTI89 was inoculated into bladders of 7- to 8-week-old CBA/CaJ mice. (B–D) Scatter plots show that when animals received no antibiotic treatment (Abx) (black), urine collected on day 1, 4, or 6 featured high bacterial titers. While low doses (25 and 125 μg) of sisomicin (red) and N1MS (green) reduced bacterial growth, high doses of both drugs (625 μg) effectively prevented bacterial growth. (E and F) Homogenates of bladders and kidneys from mice whose bladders were inoculated with E. coli were examined for bacterial growth. Whereas tissues feature high bacterial titers in the absence of antibiotic treatment, both sisomicin and N1MS reduced colony formation, especially at the higher doses. n = 10 for B–F.