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Identification of Aspergillus fumigatus UDP-Galactopyranose Mutase Inhibitors
Julia S Martin Del Campo1, Meital Eckshtain-Levi1, Nancy J Vogelaar2
1Department of Biochemistry, Virginia Tech, Blacksburg, VA, 24061, USA.
Abstract:
Aspergillus fumigatus is an opportunistic human pathogen responsible for deadly, invasive infections in immunocompromised patients. The A. fumigatus cell wall is a complex network of polysaccharides among them galactofuran, which is absent in humans. UDP-galactopyranose mutase (UGM) catalyzes the conversion of UDP-galactofuranose (UDP-Galf) to UDP-galactopyranose (UDP-Galp) and is an important virulence factor. UGM is a flavin-dependent enzyme that requires the reduced flavin for activity; flavin reduction is achieved by reaction with NADPH. The aim of this work was to discover inhibitors of UGM by targeting the NADPH binding site using an ADP-TAMRA probe in a high-throughput screening assay. The flavonoids (2S)-hesperetin and (2S)-naringenin were validated as competitive inhibitors of UGM against NADPH with Ki values of 6 µM and 74 µM, respectively. To gain insight into the active chemical substituents involved in the inhibition of UGM, several derivatives of these inhibitors were studied. The results show that the hydroxyl groups of (2S)-hesperetin are important for inhibition, in particular the phenyl-chroman moiety. Congo red susceptibility assay and growth temperature effects showed that these compounds affected cell wall biosynthesis in A. fumigatus. This work is the first report of inhibition studies on UGM from eukaryotic human pathogens.
Insights
Researchers identified flavonoids, hesperetin and naringenin, as inhibitors of UDP-galactopyranose mutase (UGM), a key virulence factor in Aspergillus fumigatus. These compounds target the enzyme
Area of Science:
- Mycology
- Biochemistry
- Medicinal Chemistry
Background:
- Aspergillus fumigatus causes life-threatening invasive infections in immunocompromised individuals.
- The fungal cell wall contains unique polysaccharides like galactofuran, making its biosynthesis enzymes potential therapeutic targets.
- UDP-galactopyranose mutase (UGM) is a crucial enzyme in galactofuran synthesis and a significant virulence factor for A. fumigatus.
Purpose of the Study:
- To discover novel inhibitors of A. fumigatus UGM by targeting its NADPH binding site.
- To investigate the structure-activity relationships of flavonoid inhibitors against UGM.
- To assess the impact of identified inhibitors on fungal cell wall biosynthesis and viability.
Main Methods:
- High-throughput screening using an ADP-TAMRA probe to identify UGM inhibitors.
- Enzyme inhibition assays to determine inhibitor potency (Ki values) against NADPH.
- Synthesis and evaluation of UGM inhibitor derivatives to understand structure-activity relationships.
- Congo red susceptibility assays and growth temperature studies to assess effects on fungal cell wall biosynthesis.
Main Results:
- Flavonoids (2S)-hesperetin and (2S)-naringenin were identified as competitive inhibitors of UGM with Ki values of 6 µM and 74 µM, respectively.
- The hydroxyl groups and phenyl-chroman moiety of (2S)-hesperetin were found to be critical for UGM inhibition.
- The identified compounds demonstrated an impact on A. fumigatus cell wall biosynthesis.
Conclusions:
- This study presents the first report of UGM inhibition in a eukaryotic human pathogen, A. fumigatus.
- (2S)-hesperetin and (2S)-naringenin are promising lead compounds for developing new antifungal therapies targeting UGM.
- Inhibiting UGM represents a viable strategy to disrupt A. fumigatus cell wall integrity and combat invasive infections.
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