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.
Highlights
Aspergillus spp. are ubiquitous filamentous fungi and together with three other genera (Candida, Cryptococcus, and Pneumocystis) account for more than 90% of invasive fungal infections worldwide.[1]
BLAST searches using the Arabidopsis thaliana NMT127 or Aspergillus nidulans NMT28 sequences predicted the presence of an nmt gene (AFUA_4G08070) in the A. f umigatus genome
The 1479 bp mRNA encodes a protein of 492 amino acids (UniProt: Q9UVX3) sharing 50%, 52%, 38%, and 44% sequence identity with the NMTs of C. albicans, S. cerevisiae, Leishmania major, and Homo sapiens (Supporting Information Figure 1), respectively
Summary
Aspergillus spp. are ubiquitous filamentous fungi and together with three other genera (Candida, Cryptococcus, and Pneumocystis) account for more than 90% of invasive fungal infections worldwide.[1] While invasive aspergillosis due to A. f umigatus is estimated to affect over 200 000 people globally each year, a further 3 million are affected by chronic pulmonary aspergillosis.[1] At present, treatment is limited to three antifungal classes: polyenes, azoles, and echinocandins. A substantial pool of new chemical starting points for inhibitors of NMTs from parasites has recently been described.[15−21] So far, NMT in filamentous fungi such as A. f umigatus remains uncharacterized orthologues in other fungal pathogens such as Candida albicans[22] and Cryptococcus neoformans[23] are essential for viability. We show that NMT is a potential drug target in A. f umigatus
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