Synthesis, antimicrobial activity, attenuation of aminoglycoside resistance in MRSA, and ribosomal A-site binding of pyrene-neomycin conjugates

Sandra Story, Michael J. Skriba, Krishnagopal Maiti, Ranjan Nihar Ranjan, Natalya N. Degtyareva, Keith D. Green, Verjine Khodaverdian, Adegboyega K. Oyelere, Sylvie Garneau-Tsodikova, Dev P. Arya

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

The development of new ligands that have comparable or enhanced therapeutic efficacy relative to current drugs is vital to the health of the global community in the short and long term. One strategy to accomplish this goal is to functionalize sites on current antimicrobials to enhance specificity and affinity while abating resistance mechanisms of infectious organisms. Herein, we report the synthesis of a series of pyrene-neomycin B (PYR-NEO) conjugates, their binding affinity to A-site RNA targets, resistance to aminoglycoside-modifying enzymes (AMEs), and antibacterial activity against a wide variety of bacterial strains of clinical relevance. PYR-NEO conjugation significantly alters the affinities of NEO for bacterial A-site targets. The conjugation of PYR to NEO significantly increased the resistance of NEO to AME modification. PYR-NEO conjugates exhibited broad-spectrum activity towards Gram-positive bacteria, including improved activity against NEO-resistant methicillin-resistant Staphylococcus aureus (MRSA) strains.

Original languageEnglish
Pages (from-to)381-393
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Volume163
DOIs
StatePublished - Feb 1 2019

Bibliographical note

Publisher Copyright:
© 2018 Elsevier Masson SAS

Keywords

  • Aminoglycoside
  • MRSA
  • Neomycin
  • RNA
  • Ribosome

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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