Fang Wenxia, Robinson David A, Raimi Olawale G, Blair David E, Harrison Justin R, Lockhart Deborah E A, Torrie Leah S, Ruda Gian Filippo, Wyatt Paul G, Gilbert Ian H, van Aalten Daan M F
†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.
ACS Chem Biol. 2015 Jun 19;10(6):1425-34. doi: 10.1021/cb5008647. Epub 2015 Feb 27.
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.
丝状真菌感染的治疗依赖于有限的抗真菌药物种类。迫切需要具有新型作用方式的化合物。N-肉豆蔻酰化是真核生物蛋白质普遍存在的修饰。N-肉豆蔻酰转移酶（NMT）已被认为是原生动物和酵母中的潜在治疗靶点。在此，我们表明丝状真菌病原体烟曲霉拥有一种对生存至关重要的活性NMT酶。令人惊讶的是，该基因的部分抑制揭示了N-肉豆蔻酰化对细胞壁形态的下游影响。筛选抑制剂文库导致发现了一种吡唑磺酰胺化合物，该化合物可抑制该酶，并在部分抑制nmt的条件下具有杀菌作用。结合显示抑制剂结合在肽底物口袋中的晶体复合物，我们提供了NMT是烟曲霉潜在药物靶点的证据。
