Issue 9, 2021

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

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.

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

Supplementary files

Article information

Article type
Research Article
Submitted
25 Jun 2021
Accepted
03 Aug 2021
First published
05 Aug 2021

RSC Med. Chem., 2021,12, 1585-1591

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

M. G. Pirrone, S. N. Hobbie, A. Vasella, E. C. Böttger and D. Crich, RSC Med. Chem., 2021, 12, 1585 DOI: 10.1039/D1MD00214G

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