Small Molecule
Antivirulents Targeting the Iron-Regulated
Heme Oxygenase (HemO) of <i>P. aeruginosa</i>
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Abstract
Bacteria require iron for survival
and virulence and employ several
mechanisms including utilization of the host heme containing proteins.
The final step in releasing iron is the oxidative cleavage of heme
by HemO. A recent computer aided drug design (CADD) study identified
several inhibitors of the bacterial HemOs. Herein we report the near
complete HN, N, CO, Cα, and Cβ chemical shift assignment
of the <i>P. aeruginosa</i> HemO in the absence and presence
of inhibitors (<i>E</i>)-3-(4-(phenylamino)phenylcarbamoyl)acrylic
acid (<b>3</b>) and (<i>E</i>)-<i>N</i>′-(4-(dimethylamino)benzylidene)
diazenecarboximidhydrazide (<b>5</b>). The NMR data confirm
that the inhibitors bind within the heme pocket of HemO consistent
with in silico molecular dynamic simulations. Both inhibitors and
the phenoxy derivative of <b>3</b> have activity against <i>P. aeruginosa</i> clinical isolates. Furthermore, <b>5</b> showed antimicrobial activity in the in vivo C. elegans curing assay. Thus, targeting virulence mechanisms required within
the host is a viable antimicrobial strategy for the development of
novel antivirulants