N-myristoyltransferase is a cell wall target in Aspergillus fumigatus

Wenxia Fang, David A. Robinson, 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 (Lead / Corresponding author)

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    16 Citations (Scopus)

    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
    DOIs
    Publication statusPublished - 19 Jun 2015

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