Structure-Activity Relationships for 5′′ Modifications of 4,5-Aminoglycoside Antibiotics
dc.contributor.author
Quirke, Jonathan C. K.
dc.contributor.author
Sati, Girish C.
dc.contributor.author
Sonousi, Amr
dc.contributor.author
Gysin, Marina
dc.contributor.author
Haldimann, Klara
dc.contributor.author
Böttger, Erik C.
dc.contributor.author
Vasella, Andrea
dc.contributor.author
Hobbie, Sven N.
dc.contributor.author
Crich, David
dc.date.accessioned
2022-08-09T06:12:37Z
dc.date.available
2022-07-13T03:04:56Z
dc.date.available
2022-08-09T06:12:37Z
dc.date.issued
2022-07-05
dc.identifier.issn
1860-7179
dc.identifier.issn
1860-7187
dc.identifier.other
10.1002/cmdc.202200120
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/557708
dc.description.abstract
Modification at the 5’’-position of 4,5-disubstituted aminoglycoside antibiotics (AGAs) to circumvent inactivation by aminoglycoside modifying enzymes (AMEs) is well known. Such modifications, however, unpredictably impact activity and affect target selectivity thereby hindering drug development. A survey of 5’’-modifications of the 4,5-AGAs and the related 5-O-furanosyl apramycin derivatives is presented. In the neomycin and the apralog series, all modifications were well-tolerated, but other 4,5-AGAs require a hydrogen bonding group at the 5’’-position for maintenance of antibacterial activity. The 5’’-amino modification resulted in parent-like activity, but reduced selectivity against the human cytosolic decoding A site rendering this modification unfavorable in paromomycin, propylamycin, and ribostamycin. Installation of a 5’’-formamido group and, to a lesser degree, a 5’’-ureido group resulted in parent-like activity without loss of selectivity. These lessons will aid the design of next-generation AGAs capable of circumventing AME action while maintaining high antibacterial activity and target selectivity.
en_US
dc.language.iso
en
en_US
dc.publisher
Wiley-VCH
en_US
dc.title
Structure-Activity Relationships for 5′′ Modifications of 4,5-Aminoglycoside Antibiotics
en_US
dc.type
Journal Article
dc.date.published
2022-04-06
ethz.journal.title
ChemMedChem
ethz.journal.volume
17
en_US
ethz.journal.issue
13
en_US
ethz.journal.abbreviated
ChemMedChem
ethz.pages.start
e202200120
en_US
ethz.size
12 p.
en_US
ethz.identifier.scopus
ethz.publication.place
Weinheim
en_US
ethz.publication.status
published
en_US
ethz.date.deposited
2022-07-13T03:05:16Z
ethz.source
SCOPUS
ethz.eth
yes
en_US
ethz.availability
Metadata only
en_US
ethz.rosetta.installDate
2022-08-09T06:12:45Z
ethz.rosetta.lastUpdated
2022-08-09T06:12:45Z
ethz.rosetta.versionExported
true
ethz.COinS
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Journal Article [133720]