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Influence of ring size in conformationally restricted ring I analogs of paromomycin on antiribosomal and antibacterial activity


Pirrone, Michael G; Hobbie, Sven N; Vasella, Andrea; Böttger, Erik C; Crich, David (2021). Influence of ring size in conformationally restricted ring I analogs of paromomycin on antiribosomal and antibacterial activity. RSC Medicinal Chemistry, 12(9):1585-1591.

Abstract

In order to further investigate the importance of the conformation of the ring I side chain in aminoglycoside antibiotic binding to the ribosomal target several derivatives of paromomycin were designed with conformationally locked side chains. By changing the size of the appended ring between O-4' and C-6' used to restrict the motion of the side chain, the position of the C-6' hydroxy group was fine tuned to probe for the optimal conformation for inhibition of the ribosome. While the changes in orientation of the 6'-hydroxy group cannot be completely dissociated from the size and hydrophobicity of the conformation-restricting ring, overall, it is apparent that the preferred conformation of the ring I side chain for interaction with A1408 in the decoding A site of the bacterial ribosome is an ideal gt conformation, which results in the highest antimicrobial activity as well as increased selectivity for bacterial over eukaryotic ribosomes.

Abstract

In order to further investigate the importance of the conformation of the ring I side chain in aminoglycoside antibiotic binding to the ribosomal target several derivatives of paromomycin were designed with conformationally locked side chains. By changing the size of the appended ring between O-4' and C-6' used to restrict the motion of the side chain, the position of the C-6' hydroxy group was fine tuned to probe for the optimal conformation for inhibition of the ribosome. While the changes in orientation of the 6'-hydroxy group cannot be completely dissociated from the size and hydrophobicity of the conformation-restricting ring, overall, it is apparent that the preferred conformation of the ring I side chain for interaction with A1408 in the decoding A site of the bacterial ribosome is an ideal gt conformation, which results in the highest antimicrobial activity as well as increased selectivity for bacterial over eukaryotic ribosomes.

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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 > Pharmaceutical Science
Life Sciences > Drug Discovery
Physical Sciences > Organic Chemistry
Language:English
Date:23 September 2021
Deposited On:17 Dec 2021 07:59
Last Modified:25 Feb 2024 02:51
Publisher:Royal Society of Chemistry
ISSN:2632-8682
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1039/d1md00214g
PubMed ID:34671740
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