Dissociating antibacterial from ototoxic effects of gentamicin C-subtypes
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.
Errataetall: |
ErratumIn: Proc Natl Acad Sci U S A. 2021 Sep 14;118(37):. - PMID 34493689 |
---|---|
Medienart: |
E-Artikel |
Erscheinungsjahr: |
2020 |
---|---|
Erschienen: |
2020 |
Enthalten in: |
Zur Gesamtaufnahme - volume:117 |
---|---|
Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 117(2020), 51 vom: 22. Dez., Seite 32423-32432 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
O'Sullivan, Mary E [VerfasserIn] |
---|
Links: |
---|
Anmerkungen: |
Date Completed 08.02.2021 Date Revised 10.09.2021 published: Print-Electronic ErratumIn: Proc Natl Acad Sci U S A. 2021 Sep 14;118(37):. - PMID 34493689 Citation Status MEDLINE |
---|
doi: |
10.1073/pnas.2013065117 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM318543931 |
---|
LEADER | 01000naa a22002652 4500 | ||
---|---|---|---|
001 | NLM318543931 | ||
003 | DE-627 | ||
005 | 20231225165553.0 | ||
007 | cr uuu---uuuuu | ||
008 | 231225s2020 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1073/pnas.2013065117 |2 doi | |
028 | 5 | 2 | |a pubmed24n1061.xml |
035 | |a (DE-627)NLM318543931 | ||
035 | |a (NLM)33288712 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a O'Sullivan, Mary E |e verfasserin |4 aut | |
245 | 1 | 0 | |a Dissociating antibacterial from ototoxic effects of gentamicin C-subtypes |
264 | 1 | |c 2020 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Completed 08.02.2021 | ||
500 | |a Date Revised 10.09.2021 | ||
500 | |a published: Print-Electronic | ||
500 | |a ErratumIn: Proc Natl Acad Sci U S A. 2021 Sep 14;118(37):. - PMID 34493689 | ||
500 | |a Citation Status MEDLINE | ||
520 | |a 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 | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Research Support, N.I.H., Extramural | |
650 | 4 | |a Research Support, Non-U.S. Gov't | |
650 | 4 | |a aminoglycoside | |
650 | 4 | |a gentamicin | |
650 | 4 | |a hair cell | |
650 | 4 | |a mechanotransducer channel | |
650 | 4 | |a ototoxicity | |
650 | 7 | |a Anti-Bacterial Agents |2 NLM | |
650 | 7 | |a Gentamicins |2 NLM | |
650 | 7 | |a Ion Channels |2 NLM | |
650 | 7 | |a gentamicin C |2 NLM | |
650 | 7 | |a 11097-82-8 |2 NLM | |
650 | 7 | |a Sisomicin |2 NLM | |
650 | 7 | |a X55XSL74YQ |2 NLM | |
700 | 1 | |a Song, Yohan |e verfasserin |4 aut | |
700 | 1 | |a Greenhouse, Robert |e verfasserin |4 aut | |
700 | 1 | |a Lin, Randy |e verfasserin |4 aut | |
700 | 1 | |a Perez, Adela |e verfasserin |4 aut | |
700 | 1 | |a Atkinson, Patrick J |e verfasserin |4 aut | |
700 | 1 | |a MacDonald, Jacob P |e verfasserin |4 aut | |
700 | 1 | |a Siddiqui, Zehra |e verfasserin |4 aut | |
700 | 1 | |a Lagasca, Dennis |e verfasserin |4 aut | |
700 | 1 | |a Comstock, Kate |e verfasserin |4 aut | |
700 | 1 | |a Huth, Markus E |e verfasserin |4 aut | |
700 | 1 | |a Cheng, Alan G |e verfasserin |4 aut | |
700 | 1 | |a Ricci, Anthony J |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Proceedings of the National Academy of Sciences of the United States of America |d 1915 |g 117(2020), 51 vom: 22. Dez., Seite 32423-32432 |w (DE-627)NLM000008982 |x 1091-6490 |7 nnns |
773 | 1 | 8 | |g volume:117 |g year:2020 |g number:51 |g day:22 |g month:12 |g pages:32423-32432 |
856 | 4 | 0 | |u http://dx.doi.org/10.1073/pnas.2013065117 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 117 |j 2020 |e 51 |b 22 |c 12 |h 32423-32432 |