Tobramycin Variants with Enhanced Ribosome-Targeting Activity

Marina Y. Fosso, Hongkun Zhu, Keith D. Green, Sylvie Garneau-Tsodikova, Kurt Fredrick

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

With the increased evolution of aminoglycoside (AG)-resistant bacterial strains, the need to develop AGs with 1) enhanced antimicrobial activity, 2) the ability to evade resistance mechanisms, and 3) the capability of targeting the ribosome with higher efficiency is more and more pressing. The chemical derivatization of the naturally occurring tobramycin (TOB) by attachment of 37 different thioether groups at the 6′′-position led to the identification of generally poorer substrates of TOB-targeting AG-modifying enzymes (AMEs). Thirteen of these displayed better antibacterial activity than the parent TOB while retaining ribosome-targeting specificity. Analysis of these compounds in vitro shed light on the mechanism by which they act and revealed three with clearly enhanced ribosome-targeting activity.

Original languageEnglish
Pages (from-to)1565-1570
Number of pages6
JournalChemBioChem
Volume16
Issue number11
DOIs
StatePublished - Jul 1 2015

Bibliographical note

Publisher Copyright:
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Keywords

  • aminoglycoside
  • antibacterial agents
  • bacterial resistance
  • drug-modifying enzymes
  • translocation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry

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