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

Yi Jin, Derrick Watkins, Natalya N. Degtyareva, Keith D. Green, Meredith N. Spano, Sylvie Garneau-Tsodikova, Dev P. Arya

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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.

Original languageEnglish
Pages (from-to)164-169
Number of pages6
JournalMedChemComm
Volume7
Issue number1
DOIs
StatePublished - 2016

Bibliographical note

Publisher Copyright:
© The Royal Society of Chemistry 2016.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry

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