title: Iminoguanidines as Allosteric Inhibitors of the Iron-Regulated Heme Oxygenase (HemO) of Pseudomonas aeruginosa.
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).
authors.affiliation: University of Maryland Computer-Aided Drug Design Center, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland , Baltimore, Maryland 21201, United States.
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Heinzl
authors.affiliation: University of Maryland Computer-Aided Drug Design Center, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland , Baltimore, Maryland 21201, United States.
authors.forename: Weiliang
authors.initials: W
authors.lastname: Huang
authors.affiliation: University of Maryland Computer-Aided Drug Design Center, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland , Baltimore, Maryland 21201, United States.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Yu
authors.affiliation: University of Maryland Computer-Aided Drug Design Center, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland , Baltimore, Maryland 21201, United States.
authors.forename: Bennett J
authors.initials: BJ
authors.lastname: Giardina
authors.affiliation: University of Maryland Computer-Aided Drug Design Center, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland , Baltimore, Maryland 21201, United States.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: University of Maryland Computer-Aided Drug Design Center, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland , Baltimore, Maryland 21201, United States.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: MacKerell
authors.affiliation: University of Maryland Computer-Aided Drug Design Center, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland , Baltimore, Maryland 21201, United States.
authors.forename: Angela
authors.initials: A
authors.lastname: Wilks
authors.affiliation: University of Maryland Computer-Aided Drug Design Center, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland , Baltimore, Maryland 21201, United States.
authors.forename: Fengtian
authors.initials: F
authors.lastname: Xue
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019791:Guanidine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D006419:Heme Oxygenase (Decyclizing); D019791:Guanidine