Iminoguanidines as Allosteric Inhibitors of the Iron-Regulated Heme Oxygenase (HemO) of Pseudomonas aeruginosa.

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TitleIminoguanidines as Allosteric Inhibitors of the Iron-Regulated Heme Oxygenase (HemO) of Pseudomonas aeruginosa.
Publication TypeJournal Article
Year of Publication2016
AuthorsHeinzl, GA, Huang, W, Yu, W, Giardina, BJ, Zhou, Y, Mackerell, AD, Wilks, A, Xue, F
JournalJ Med Chem
Volume59
Issue14
Pagination6929-42
Date Published2016 Jul 28
ISSN1520-4804
KeywordsAllosteric Regulation, Anti-Bacterial Agents, Dose-Response Relationship, Drug, Enzyme Inhibitors, Guanidine, Heme Oxygenase (Decyclizing), Microbial Sensitivity Tests, Models, Molecular, Molecular Structure, Pseudomonas aeruginosa, Structure-Activity Relationship
Abstract

New therapeutic targets are required to combat multidrug resistant infections, such as the iron-regulated heme oxygenase (HemO) of Pseudomonas aeruginosa, 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 23 showed a binding affinity of 5.7 μM and an MIC50 of 52.3 μg/mL against P. aeruginosa PAO1. An in cellulo activity assay was developed by coupling HemO activity to a biliverdin-IXα-dependent infrared fluorescent protein, in which compound 23 showed an EC50 of 11.3 μM. The compounds showed increased activity against clinical isolates of P. aeruginosa, 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).

DOI10.1021/acs.jmedchem.6b00757
Alternate JournalJ. Med. Chem.
PubMed ID27353344
PubMed Central IDPMC5080841
Grant ListR01 AI102883 / AI / NIAID NIH HHS / United States
T32 GM066706 / GM / NIGMS NIH HHS / United States