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 1

Novel aminoglycosides have diminished ototoxicity in vitro.

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Novel aminoglycosides have diminished ototoxicity in vitro. (A) Schemati...
(A) Schematic showing that the nonselective hair cell MET channels are permeable to cations (calcium and aminoglycosides). (B) The sisomicin compound is comprised of 3 rings. Targeted modifications were made to the amine groups on the second (N1) and third rings (N3”). Three distinct chemical moieties were used to modify sisomicin: MS, PS, and BZ. N1BZ: R1=BZ, R2=H; N1MS: R1=MS, R2=H; N1PS: R1=PS, R2=H; N1,3”BZ: R1=BZ, R2=BZ; N1,3”MS: R1=MS, R2=MS; N1,3”PS: R1=PS, R2=PS; N3”BZ: R1=H, R2=BZ; N3”MS: R1=H, R2=MS; N3”PS: R1=H, R2=PS. (C) Experimental paradigm using cochleae from P4 rats to assess ototoxicity of sisomicin and its derivatives in vitro. AG, aminoglycoside. (D) Representative micrograph of the basal turn of undamaged, cultured cochleae, showing myosin VIIa–expressing outer and inner hair cells (OHC and IHC). (E) Sisomicin-treated (200 μM) cochleae showing dramatic loss of outer hair cells. (F) Hair cells were preserved in cochleae cultured with N1MS (200 μM). (G) Hair cell survival (normalized to undamaged, cultured cochleae) in cochleae (divided into 3 regions [base, middle, and apex]) treated with sisomicin or its derivatives (all 200 μM). Sisomicin caused a basal-apical gradient of hair cell loss, whereas treatment with each of the 9 sisomicin derivatives caused less hair cell loss. (H) Dose-response analyses comparing dosage of sisomicin and N1MS treatment to hair cell loss in the basal turn of the cochlea. Sigmoidal best fits estimated KDs of sisomicin and N1MS to be 100 μM and 1.7 mM, respectively. Data are shown as average ± SEM. n = 4–10 for G and H. Scale bar: 25 μm.