title: N-myristoyltransferase is a cell wall target in Aspergillus fumigatus.
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.
authors.affiliation: †Division of Molecular Microbiology, ‡Division of Biological Chemistry and Drug Discovery, §MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, United Kingdom.
authors.forename: Wenxia
authors.initials: W
authors.lastname: Fang
authors.affiliation: †Division of Molecular Microbiology, ‡Division of Biological Chemistry and Drug Discovery, §MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, United Kingdom.
authors.forename: David A
authors.initials: DA
authors.lastname: Robinson
authors.affiliation: †Division of Molecular Microbiology, ‡Division of Biological Chemistry and Drug Discovery, §MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, United Kingdom.
authors.forename: Olawale G
authors.initials: OG
authors.lastname: Raimi
authors.affiliation: †Division of Molecular Microbiology, ‡Division of Biological Chemistry and Drug Discovery, §MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, United Kingdom.
authors.forename: David E
authors.initials: DE
authors.lastname: Blair
authors.affiliation: †Division of Molecular Microbiology, ‡Division of Biological Chemistry and Drug Discovery, §MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, United Kingdom.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Harrison
authors.affiliation: †Division of Molecular Microbiology, ‡Division of Biological Chemistry and Drug Discovery, §MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, United Kingdom.
authors.forename: Deborah E A
authors.initials: DE
authors.lastname: Lockhart
authors.affiliation: †Division of Molecular Microbiology, ‡Division of Biological Chemistry and Drug Discovery, §MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, United Kingdom.
authors.forename: Leah S
authors.initials: LS
authors.lastname: Torrie
authors.affiliation: †Division of Molecular Microbiology, ‡Division of Biological Chemistry and Drug Discovery, §MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, United Kingdom.
authors.forename: Gian Filippo
authors.initials: GF
authors.lastname: Ruda
authors.affiliation: †Division of Molecular Microbiology, ‡Division of Biological Chemistry and Drug Discovery, §MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, United Kingdom.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Wyatt
authors.affiliation: †Division of Molecular Microbiology, ‡Division of Biological Chemistry and Drug Discovery, §MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, United Kingdom.
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
authors.affiliation: †Division of Molecular Microbiology, ‡Division of Biological Chemistry and Drug Discovery, §MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, United Kingdom.
authors.forename: Daan M F
authors.initials: DM
authors.lastname: van Aalten
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000631:Aminopyridines / Q000737:chemistry / Q000494:pharmacology; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D020134:Catalytic Domain; D002473:Cell Wall / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology; D018360:Crystallography, X-Ray; D005656:Fungal Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017433:Protein Structure, Secondary; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D000217:Acyltransferases; D000631:Aminopyridines; D000935:Antifungal Agents; D005656:Fungal Proteins; D011720:Pyrazoles; D013449:Sulfonamides; C549249:DDD 85646; D000096926:Benzenesulfonamides; C050480:glycylpeptide N-tetradecanoyltransferase