Abstract
Aspergillus fumigatus is an opportunistic fungal pathogen and the most common causative agent of fatal invasive mycoses. The flavin-dependent monooxygenase siderophore A (SidA) catalyzes the oxygen and NADPH dependent hydroxylation of l-ornithine (l-Orn) to N5-l-hydroxyornithine in the biosynthetic pathway of hydroxamate-containing siderophores in A. fumigatus. Deletion of the gene that codes for SidA has shown that it is essential in establishing infection in mice models. Here, a fluorescence polarization high-throughput assay was used to screen a 2320 compound library for inhibitors of SidA. Celastrol, a natural quinone methide, was identified as a noncompetitive inhibitor of SidA with a MIC value of 2 μM. Docking experiments suggest that celastrol binds across the NADPH and l-Orn pocket. Celastrol prevents A. fumigatus growth in blood agar. The addition of purified ferric-siderophore abolished the inhibitory effect of celastrol. Thus, celastrol inhibits A. fumigatus growth by blocking siderophore biosynthesis through SidA inhibition.
Recommended Citation
J. S. Martín Del Campo et al., "Inhibition of the Flavin-dependent Monooxygenase Siderophore a (SidA) Blocks Siderophore Biosynthesis and Aspergillus Fumigatus Growth," ACS Chemical Biology, vol. 11, no. 11, pp. 3035 - 3042, American Chemical Society, Nov 2016.
The definitive version is available at https://doi.org/10.1021/acschembio.6b00666
Department(s)
Chemistry
International Standard Serial Number (ISSN)
1554-8937; 1554-8929
Document Type
Article - Journal
Document Version
Citation
File Type
text
Language(s)
English
Rights
© 2024 American Chemical Society, All rights reserved.
Publication Date
18 Nov 2016
PubMed ID
27588426
Comments
National Institute of General Medical Sciences, Grant R01GM094469