title: Small molecule antivirulents targeting the iron-regulated heme oxygenase (HemO) of P. aeruginosa.
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 P. aeruginosa HemO in the absence and presence of inhibitors (E)-3-(4-(phenylamino)phenylcarbamoyl)acrylic acid (3) and (E)-N'-(4-(dimethylamino)benzylidene) diazenecarboximidhydrazide (5). 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 3 have activity against P. aeruginosa clinical isolates. Furthermore, 5 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.
authors: The Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland 21201-1140, United States.
authors: Kellie
authors: K
authors: Hom
authors: Geoffrey A
authors: GA
authors: Heinzl
authors: Suntara
authors: S
authors: Eakanunkul
authors: Pedro E M
authors: PE
authors: Lopes
authors: Fengtian
authors: F
authors: Xue
authors: Alexander D
authors: AD
authors: MacKerell
authors: Angela
authors: A
authors: Wilks
mesh_terms: D000818:Animals; D001051:Apoenzymes / Q000737:chemistry; D017173:Caenorhabditis elegans; D004159:Diphenylamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005650:Fumarates / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology*; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006835:Hydrazones / Q000494:pharmacology*; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000201:enzymology / Q000472:pathogenicity; D014774:Virulence / Q000187:drug effects*
chemical_list: C581007:3-(4-(phenylamino)phenylcarbamoyl)acrylic acid; D001051:Apoenzymes; D004791:Enzyme Inhibitors; D005650:Fumarates; D006146:Guanidines; D006835:Hydrazones; C581008:N'-(4-(dimethylamino)benzylidene)diazenecarboximidhydrazide; D004159:Diphenylamine; D006419:Heme Oxygenase (Decyclizing)
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