Inhibition of the ANT(2")-Ia resistance enzyme and rescue of aminoglycoside antibiotic activity by synthetic α-hydroxytropolones

Bioorg Med Chem Lett. 2014 Nov 1;24(21):4943-7. doi: 10.1016/j.bmcl.2014.09.037. Epub 2014 Sep 19.

Abstract

Aminoglycoside-2"-O-nucleotidyltransferase ANT(2")-Ia is an aminoglycoside resistance enzyme prevalent among Gram-negative bacteria, and is one of the most common determinants of enzyme-dependant aminoglycoside-resistance. The following report outlines the use of our recently described oxidopyrylium cycloaddition/ring-opening strategy in the synthesis and profiling of a library of synthetic α-hydroxytropolones against ANT(2")-Ia. In addition, we show that two of these synthetic constructs are capable of rescuing gentamicin activity against ANT-(2")-Ia-expressing bacteria.

Keywords: Aminoglycoside-2″-O-nucleotidyltransferase; Aminoglycosides; Bacterial Resistance; Gentamicin; α-Hydroxytropolones.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Drug Resistance, Bacterial / drug effects*
  • Escherichia coli / drug effects*
  • Gentamicins / pharmacology*
  • Models, Chemical
  • Molecular Structure
  • Nucleotidyltransferases / antagonists & inhibitors*
  • Nucleotidyltransferases / metabolism
  • Tropolone / chemistry
  • Tropolone / pharmacology*

Substances

  • Anti-Bacterial Agents
  • Gentamicins
  • Tropolone
  • Nucleotidyltransferases
  • gentamicin 2''-nucleotidyltransferase