Synthesis and evaluation of hetero- and homodimers of ribosome-targeting antibiotics: Antimicrobial activity, in vitro inhibition of translation, and drug resistance

Yifat Berkov-Zrihen, Keith D. Green, Kristin J. Labby, Mark Feldman, Sylvie Garneau-Tsodikova, Micha Fridman

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

In this study, we describe the synthesis of a full set of homo- and heterodimers of three intact structures of different ribosome-targeting antibiotics: tobramycin, clindamycin, and chloramphenicol. Several aspects of the biological activity of the dimeric structures were evaluated including antimicrobial activity, inhibition of in vitro bacterial protein translation, and the effect of dimerization on the action of several bacterial resistance mechanisms that deactivate tobramycin and chloramphenicol. This study demonstrates that covalently linking two identical or different ribosome-targeting antibiotics may lead to (i) a broader spectrum of antimicrobial activity, (ii) improved inhibition of bacterial translation properties compared to that of the parent antibiotics, and (iii) reduction in the efficacy of some drug-modifying enzymes that confer high levels of resistance to the parent antibiotics from which the dimers were derived.

Original languageEnglish
Pages (from-to)5613-5625
Number of pages13
JournalJournal of Medicinal Chemistry
Volume56
Issue number13
DOIs
StatePublished - Jul 11 2013

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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