Small molecule antivirulents targeting the iron-regulated heme oxygenase (HemO) of P. aeruginosa.

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TitleSmall molecule antivirulents targeting the iron-regulated heme oxygenase (HemO) of P. aeruginosa.
Publication TypeJournal Article
Year of Publication2013
AuthorsHom, K, Heinzl, GA, Eakanunkul, S, Lopes, PEM, Xue, F, Mackerell, AD, Wilks, A
JournalJ Med Chem
Volume56
Issue5
Pagination2097-109
Date Published2013 Mar 14
ISSN1520-4804
KeywordsAnimals, Apoenzymes, Caenorhabditis elegans, Diphenylamine, Enzyme Inhibitors, Fumarates, Guanidines, Heme Oxygenase (Decyclizing), Hydrazones, Models, Molecular, Molecular Docking Simulation, Molecular Dynamics Simulation, Nuclear Magnetic Resonance, Biomolecular, Pseudomonas aeruginosa, Virulence
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.

DOI10.1021/jm301819k
Alternate JournalJ. Med. Chem.
PubMed ID23379514
PubMed Central IDPMC3643010
Grant ListR01 AI085535 / AI / NIAID NIH HHS / United States
R01 AI055912 / AI / NIAID NIH HHS / United States
AI-85535 / AI / NIAID NIH HHS / United States
AI-55912 / AI / NIAID NIH HHS / United States
R56 AI055912 / AI / NIAID NIH HHS / United States