Designer aminoglycosides prevent cochlear hair cell loss and hearing loss.

Huth, Markus; Han, Kyu-Hee; Sotoudeh, Kayvon; Hsieh, Yi-Ju; Effertz, Thomas; Vu, Andrew A; Verhoeven, Sarah; Hsieh, Michael H; Greenhouse, Robert; Cheng, Alan G; Ricci, Anthony J (2015). Designer aminoglycosides prevent cochlear hair cell loss and hearing loss. Journal of clinical investigation, 125(2), pp. 583-592. American Society for Clinical Investigation 10.1172/JCI77424

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Head Organs and Neurology (DKNS) > Clinic of Ear, Nose and Throat Disorders (ENT)

UniBE Contributor:

Huth, Markus

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0021-9738

Publisher:

American Society for Clinical Investigation

Language:

English

Submitter:

Lilian Tschan

Date Deposited:

01 Apr 2015 10:46

Last Modified:

01 Apr 2015 10:46

Publisher DOI:

10.1172/JCI77424

PubMed ID:

25555219

BORIS DOI:

10.7892/boris.65614

URI:

https://boris.unibe.ch/id/eprint/65614

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