1 research outputs found
Iminoguanidines as Allosteric Inhibitors of the Iron-Regulated Heme Oxygenase (HemO) of <i>Pseudomonas aeruginosa</i>
New therapeutic targets
are required to combat multidrug resistant
infections, such as the iron-regulated heme oxygenase (HemO) of <i>Pseudomonas aeruginosa</i>, due to links between iron and virulence
and dependence on heme as an iron source during infection. Herein
we report the synthesis and activity of a series of iminoguanidine-based
inhibitors of HemO. Compound <b>23</b> showed a binding affinity
of 5.7 μM and an MIC<sub>50</sub> of 52.3 μg/mL against <i>P. aeruginosa</i> PAO1. An in cellulo activity assay was developed
by coupling HemO activity to a biliverdin-IXα-dependent infrared
fluorescent protein, in which compound <b>23</b> showed an EC<sub>50</sub> of 11.3 μM. The compounds showed increased activity
against clinical isolates of <i>P. aeruginosa</i>, further
confirming the target pathway. This class of inhibitors acts by binding
to an allosteric site; the novel binding site is proposed in silico
and supported by saturation transfer difference (STD) NMR as well
as by hydrogen exchange mass spectrometry (HXMS)