Issue 1, 2016

Arginine-linked neomycin B dimers: synthesis, rRNA binding, and resistance enzyme activity

Abstract

The nucleotides comprising the ribosomal decoding center are highly conserved, as they are important for maintaining translational fidelity. The bacterial A-site has a small base variation as compared with the human analogue, allowing aminoglycoside (AG) antibiotics to selectively bind within this region of the ribosome and negatively affect microbial protein synthesis. Here, by using a fluorescence displacement screening assay, we demonstrate that neomycin B (NEO) dimers connected by L-arginine-containing linkers of varying length and composition bind with higher affinity to model A-site RNAs compared to NEO, with IC50 values ranging from ~40–70 nM, and that a certain range of linker lengths demonstrates a clear preference for the bacterial A-site RNA over the human analogue. Furthermore, AG-modifying enzymes (AMEs), such as AG O-phosphotransferases, which are responsible for conferring antibiotic resistance in many types of infectious bacteria, demonstrate markedly reduced activity against several of the L-arginine-linked NEO dimers in vitro. The antimicrobial activity of these dimers against several bacterial strains is weaker than that of the parent NEO.

Graphical abstract: Arginine-linked neomycin B dimers: synthesis, rRNA binding, and resistance enzyme activity

Supplementary files

Article information

Article type
Concise Article
Submitted
23 Sep 2015
Accepted
21 Oct 2015
First published
03 Nov 2015

Med. Chem. Commun., 2016,7, 164-169

Arginine-linked neomycin B dimers: synthesis, rRNA binding, and resistance enzyme activity

Y. Jin, D. Watkins, N. N. Degtyareva, K. D. Green, M. N. Spano, S. Garneau-Tsodikova and D. P. Arya, Med. Chem. Commun., 2016, 7, 164 DOI: 10.1039/C5MD00427F

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