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Structure-Activity Relationships for 5'' Modifications of 4,5-Aminoglycoside Antibiotics


Quirke, Jonathan C K; Sati, Girish C; Sonousi, Amr; Gysin, Marina; Haldimann, Klara; Böttger, Erik C; Vasella, Andrea; Hobbie, Sven N; Crich, David (2022). Structure-Activity Relationships for 5'' Modifications of 4,5-Aminoglycoside Antibiotics. ChemMedChem, 17(13):e202200120.

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.

Keywords: aminoglycoside modifying enzymes; antibacterial; antiribosomal; ototoxicity

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.

Keywords: aminoglycoside modifying enzymes; antibacterial; antiribosomal; ototoxicity

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Microbiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Life Sciences > Biochemistry
Life Sciences > Molecular Medicine
Life Sciences > Pharmacology
Life Sciences > Drug Discovery
Life Sciences > General Pharmacology, Toxicology and Pharmaceutics
Physical Sciences > Organic Chemistry
Language:English
Date:5 July 2022
Deposited On:31 May 2022 13:26
Last Modified:29 Jan 2024 02:40
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:1860-7179
OA Status:Closed
Publisher DOI:https://doi.org/10.1002/cmdc.202200120
PubMed ID:35385605
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