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.

Inhibition of N‐myristoyltransferase1 affects dengue virus replication

“…Several studies have investigated the biology and pathogenesis of NMT from malaria and leishmania within its potential as a novel drug target by exploiting the inhibition effect observed when NMT expression is disrupted (Banerjee, Arora, & Murty, ; Bell et al., ; Brannigan et al., ; Tate, Bell, Rackham, & Wright, ). Furthermore, recognition of NMT as a cell wall target of Aspergillus fumigatus infection has also identified NMT as a potential therapeutic drug target (Fang et al., ; Valiante, Macheleidt, Foge, & Brakhage, ), and NMT has been identified as a novel antifungal target of Candida albicans (Sikorski et al., ; Wiegand et al., ). A study of the role of NMT in relation to human immunodeficiency virus proteins has revealed that the myristoylation of Gag and Nef proteins is a key for viral replication and virulence (Seaton & Smith, ).…”

All about that fat: Lipid modification of proteins in Cryptococcus neoformans

“…This irreversible modification is catalyzed by myristoyl-CoA:protein N-myristoyltransferase (NMT), an enzyme present in all organisms that have been examined to date, from yeast to humans. Because the modification is required for the correct function of substrate proteins, NMTs are essential for viability in organisms including the fungi C. albicans (Lodge et al , 1994b), A. fumigatus (Fang et al , 2015), and C. neoformans (Lodge et al , 1994a). Biochemical and structural analyses of NMTs suggest that they are potential therapeutic targets for diseases ranging from cancers to parasitic and fungal infections (Georgopapadakou, 2002; Panethymitaki et al , 2006; Das et al , 2012).…”

“…Their occurrence in pathogenic microbes had been relatively unexplored, until recent reports detailing lipid modifications of proteins from bacteria (Hicks and Galan, 2013; Ivanov and Roy, 2013), parasites (Goldston et al , 2014), and fungi. The last group includes medically important organisms such as Candida albicans (Richard et al , 2002; Piispanen et al , 2011), Aspergillus fumigatus (Fontaine et al , 2003; Fortwendel et al , 2012; Fang et al , 2015), and Cryptococcus neoformans (Selvig et al , 2013; Nichols et al , 2015; Santiago-Tirado et al , 2015). …”

Synthesis, Characterization and Antifungal Evaluation of Novel Thiochromanone Derivatives Containing Indole Skeleton

“…13) NMT participates in membrane targeting and the function of many proteins in a variety of signal transduction cascades and other critical cellular functions. 14) Moreover, NMTs are striking in their remarkable diversity of peptide substrates and diversity in the peptidebinding groove has offered potential of developing speciesspecific inhibitors. 14) As a result, NMT has been identified as a potential chemotherapeutic target enzyme for antifungal agents.…”

“…14) Moreover, NMTs are striking in their remarkable diversity of peptide substrates and diversity in the peptidebinding groove has offered potential of developing speciesspecific inhibitors. 14) As a result, NMT has been identified as a potential chemotherapeutic target enzyme for antifungal agents. 1) Previously, Sheng and colleagues 12) had prepared tetrahydrocarbazole derivatives ( Fig.…”