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 3

Sisomicin and its novel derivatives inhibit growth of different bacterial species.

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Sisomicin and its novel derivatives inhibit growth of different bacteria...
(A) Minimal inhibitory concentrations for N1MS, sisomicin, gentamicin, and tobramycin against 10 clinical isolates of E. coli showed that all 4 compounds inhibited growth of most strains. Asterisks indicate ESBL-producing strains. MIC50 and MIC90: sisomicin = 1 and >32 μg/ml; N1MS = 2 and 4 μg/ml; gentamicin = 0.5 and >32 μg/ml; tobramycin = 1 and 4 μg/ml, respectively. (B) Growth of most K. pneumoniae strains, including some ESBL-producing ones (asterisks), were inhibited by N1MS, whereas sisomicin, gentamicin, and tobramycin showed robust activities predominantly against non-ESBL-producing strains. MIC50 and MIC90: sisomicin = 1 and >32 μg/ml; N1MS = 1 and 128 μg/ml; gentamicin = 0.5 and 64 μg/ml; tobramycin = 0.5 and 32 μg/ml, respectively. (C) Sisomicin, gentamicin, and tobramycin inhibited growth of most P. aeruginosa strains, including drug-resistant strains (asterisks). N9744 is resistant to ciprofloxacin, N9750 is resistant to imipenem, and N9923 and N9749 are multidrug resistant. N1MS was inactive against most P. aeruginosa strains. MIC50 and MIC90: sisomicin = 0.5 and 8 μg/ml; N1MS = 16 and 64 μg/ml; gentamicin = 2 and 16 μg/ml; tobramycin = 0.5 and 4 μg/ml, respectively. (D) Growth of most S. aureus strains was suppressed by siso­micin, gentamicin, and tobramycin but not N1MS treatment. Asterisks indicate methicillin resistant strains. MIC50 and MIC90: sisomicin = 0.25 and 0.25 μg/ml; N1MS = 8 and 8 μg/ml; gentamicin = 0.5 and 0.5 μg/ml; tobramycin = 0.5 and 0.5 μg/ml, respectively. Each bar represents one experiment (n = 1).