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

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

Danielle R Hirsch  1 , Georgina Cox  2 , Michael P D'Erasmo  1 , Tushar Shakya  2 , Christine Meck  1 , Noushad Mohd  3 , Gerard D Wright  2 , Ryan P Murelli  4
Affiliations

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

Danielle R Hirsch et al. Bioorg Med Chem Lett. .

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.

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Figures

Figure 1
Figure 1
ANT(2″)Ia inhibition data of troponoids (Eli Lilly, 1982)
Figure 2
Figure 2
(A) α-Hydropolone bound to two Mn ions, adapted for clarity from crystal structure data of β-thujaplicinol bound HIV RT RNase H domain (pdb3K2B). (B) ATP mimic bound to two Mg ions, adapted for clarity from crystal structure data of the compound bound to Protein Kinase A (pdb4HPU). Structures were modified using UCSF Chimera to include only ligand and metals, and distances were also calculated from these pdb files.
Figure 3
Figure 3
ANT(2″)-Ia-inactive α-hydroxytropolone congeners that are consistent with a bimetallic binding mechanism
Figure 4
Figure 4
Checkerboard analysis of ANT(2″)-Ia inhibitors with gentamicin against an ANT(2″)-Ia-expressing E. coli along with FICI values. Also shown is data with APH(2″)-Id-expressing bacteria with β-thujaplicinol
Scheme 1
Scheme 1
Deactivation of gentamicin by the aminoglycoside resistance enzyme, ANT(2″)-Ia, through magnesium-dependent adenylation
Scheme 2
Scheme 2
Synthetic method for the synthesis of α-hydroxytropolones
Scheme 3
Scheme 3
Tridentate array of negatively charged oxygens and proposed binding mode for several dinuclear metalloenzymes. It is possible that ANT(2″)-Ia may also be bound in a similar manner.
See this image and copyright information in PMC

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