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

[img] Text
32423.full.pdf - Published Version
Restricted to registered users only
Available under License Publisher holds Copyright.

Download (1MB) | Request a copy

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.

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:

0027-8424

Publisher:

National Academy of Sciences NAS

Language:

English

Submitter:

Stefan Weder

Date Deposited:

18 Jan 2021 17:21

Last Modified:

18 Jan 2021 17:29

Publisher DOI:

10.1073/pnas.2013065117

PubMed ID:

33288712

Uncontrolled Keywords:

aminoglycoside gentamicin hair cell mechanotransducer channel ototoxicity

BORIS DOI:

10.48350/150356

URI:

https://boris.unibe.ch/id/eprint/150356

Actions (login required)

Edit item Edit item
Provide Feedback