Identification of Aspergillus fumigatus UDP-Galactopyranose Mutase Inhibitors

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dc.contributor.authorDel Campo, Julia S. Martinen
dc.contributor.authorEckshtain-Levi, Meitalen
dc.contributor.authorVogelaar, Nancy J.en
dc.contributor.authorSobrado, Pabloen
dc.contributor.departmentBiochemistryen
dc.contributor.departmentCenter for Drug Discoveryen
dc.date.accessioned2017-11-13T19:43:19Zen
dc.date.available2017-11-13T19:43:19Zen
dc.date.issued2017-09-07en
dc.description.abstractAspergillus 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 highthroughput 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.en
dc.description.sponsorshipThis work was supported by a National Institutes of Health Grant GM094469 and funds from the Fralin Life Science Institute.en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1038/s41598-017-11022-5en
dc.identifier.urihttp://hdl.handle.net/10919/80360en
dc.identifier.volume7en
dc.language.isoenen
dc.publisherNatureen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titleIdentification of Aspergillus fumigatus UDP-Galactopyranose Mutase Inhibitorsen
dc.title.serialScientific Reportsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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