Document Detail


Small molecule antivirulents targeting the iron-regulated heme oxygenase (HemO) of P. aeruginosa.
MedLine Citation:
PMID:  23379514     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Kellie Hom; Geoffrey A Heinzl; Suntara Eakanunkul; Pedro E M Lopes; Fengtian Xue; Alexander D MacKerell; Angela Wilks
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2013-03-01
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  56     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-15     Completed Date:  2013-05-14     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2097-109     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoenzymes / chemistry
Caenorhabditis elegans
Diphenylamine / analogs & derivatives*,  pharmacology
Enzyme Inhibitors / pharmacology*
Fumarates / pharmacology*
Guanidines / pharmacology*
Heme Oxygenase (Decyclizing) / antagonists & inhibitors*,  chemistry
Hydrazones / pharmacology*
Models, Molecular
Molecular Docking Simulation
Molecular Dynamics Simulation
Nuclear Magnetic Resonance, Biomolecular
Pseudomonas aeruginosa / drug effects*,  enzymology,  pathogenicity
Virulence / drug effects*
Grant Support
ID/Acronym/Agency:
AI-55912/AI/NIAID NIH HHS; AI-85535/AI/NIAID NIH HHS; R01 AI055912/AI/NIAID NIH HHS; R01 AI085535/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/3-(4-(phenylamino)phenylcarbamoyl)acrylic acid; 0/Apoenzymes; 0/Enzyme Inhibitors; 0/Fumarates; 0/Guanidines; 0/Hydrazones; 0/N'-(4-(dimethylamino)benzylidene)diazenecarboximidhydrazide; 9N3CBB0BIQ/Diphenylamine; EC 1.14.99.3/Heme Oxygenase (Decyclizing)
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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