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

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 alpha-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. (C) 2014 Elsevier Ltd. All rights reserved.