Dissociating antibacterial from ototoxic effects of gentamicin C-subtypes.

O'Sullivan, Mary E; Song, Yohan; Greenhouse, Robert; Lin, Randy; Perez, Adela; Atkinson, Patrick J; MacDonald, Jacob P; Siddiqui, Zehra; Lagasca, Dennis; Comstock, Kate; Huth, Markus E; Cheng, Alan G; Ricci, Anthony J (2020). Dissociating antibacterial from ototoxic effects of gentamicin C-subtypes. Proceedings of the National Academy of Sciences of the United States of America - PNAS, 117(51), pp. 32423-32432. National Academy of Sciences NAS 10.1073/pnas.2013065117

Text 32423.full.pdf - Published Version Restricted to registered users only Available under License Publisher holds Copyright. Download (1MB)

Gentamicin is a potent broad-spectrum aminoglycoside antibiotic whose use is hampered by ototoxic side-effects. Hospital gentamicin is a mixture of five gentamicin C-subtypes and several impurities of various ranges of nonexact concentrations. We developed a purification strategy enabling assaying of individual C-subtypes and impurities for ototoxicity and antimicrobial activity. We found that C-subtypes displayed broad and potent in vitro antimicrobial activities comparable to the hospital gentamicin mixture. In contrast, they showed different degrees of ototoxicity in cochlear explants, with gentamicin C2b being the least and gentamicin C2 the most ototoxic. Structure-activity relationships identified sites in the C4'-C6' region on ring I that reduced ototoxicity while preserving antimicrobial activity, thus identifying targets for future drug design and mechanisms for hair cell toxicity. Structure-activity relationship data suggested and electrophysiological data showed that the C-subtypes both bind and permeate the hair cell mechanotransducer channel, with the stronger the binding the less ototoxic the compound. Finally, both individual and reformulated mixtures of C-subtypes demonstrated decreased ototoxicity while maintaining antimicrobial activity, thereby serving as a proof-of-concept of drug reformulation to minimizing ototoxicity of gentamicin in patients.

Interest & Impact

Downloads

1 since deposited on 18 Jan 2021
0 in the past 12 months

Citations

5 Citations in Web of Science ®
6 Citations in Scopus

Search

in Google Scholar™

Services

Actions (login required)

Edit item

Actions (login required)

Edit item