N-myristoyltransferase is a cell wall target in Aspergillus fumigatus

Wenxia Fang, Olawale G Raimi, David E Blair, Justin R Harrison, Deborah E A Lockhart, Leah S Torrie, Gian Filippo Ruda, Paul G Wyatt, Ian H Gilbert, Daan M F van Aalten

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34 Citations (Scopus)
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Abstract

Treatment of filamentous fungal infections relies on a limited repertoire of antifungal agents. Compounds possessing novel modes of action are urgently required. N-myristoylation is a ubiquitous modification of eukaryotic proteins. The enzyme N-myristoyltransferase (NMT) has been considered a potential therapeutic target in protozoa and yeasts. Here, we show that the filamentous fungal pathogen Aspergillus fumigatus possesses an active NMT enzyme that is essential for survival. Surprisingly, partial repression of the gene revealed downstream effects of N-myristoylation on cell wall morphology. Screening a library of inhibitors led to the discovery of a pyrazole sulphonamide compound that inhibits the enzyme and is fungicidal under partially repressive nmt conditions. Together with a crystallographic complex showing the inhibitor binding in the peptide substrate pocket, we provide evidence of NMT being a potential drug target in A. fumigatus.

Original languageEnglish
Pages (from-to)1425-1434
Number of pages10
JournalACS Chemical Biology
Volume10
Issue number6
Early online date27 Feb 2015
DOIs
Publication statusPublished - 19 Jun 2015
Externally publishedYes

Bibliographical note

The authors would like to thank the European Synchrotron Radiation facility (ESRF), Grenoble, for beamline time. We thank J. James of the College of Life Sciences Microscopy Facility for his help with electron microscopy. We also thank F. Eisenhaber, Bioinformatics Institute Singapore, for predicting myristoylated proteins. This work was funded by an MRC Programme Grant (M004139) and a Wellcome Trust Senior Research Fellowship (WT087590MA) to D.M.F.v.A. D.E.A.L was supported by an MRC Clinical Research Training Fellowship (G1100430). We also would like to acknowledge the Wellcome Trust (WT077705, WT083481) for support.

Supporting Figures S1−S3, Supporting Tables S1−S4, and further details of experimental procedures. This material is available free of charge via the Internet from http://pubs.acs.org.

Keywords

  • Acyltransferases
  • Aminopyridines
  • Antifungal Agents
  • Aspergillus fumigatus
  • Catalytic Domain
  • Cell Wall
  • Crystallography, X-Ray
  • Fungal Proteins
  • Kinetics
  • Microbial Sensitivity Tests
  • Protein Binding
  • Protein Processing, Post-Translational
  • Protein Structure, Secondary
  • Pyrazoles
  • Structure-Activity Relationship
  • Sulfonamides
  • Journal Article
  • Research Support, Non-U.S. Gov't

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