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Instruments / Technical Area	Publication Details	Published	Actions
I04-Macromolecular Crystallography	Genetic validation of Aspergillus fumigatus phosphoglucomutase as a viable therapeutic target in invasive aspergillosis Kaizhou Yan , Mathew Stanley , Bartosz Kowalski , Olawale G. Raimi , Andrew T. Ferenbach , Pingzhen Wei , Wenxia Fang , Daniel M. F. Van Aalten Journal Of Biological Chemistry 4 DOI: 10.1016/j.jbc.2022.102003 Diamond Proposal Number(s): [19844] Open Access Show Abstract ▼ Abstract: Aspergillus fumigatus is the causative agent of invasive aspergillosis, an infection with mortality rates of up to 50%. The glucan-rich cell wall of A. fumigatus is a protective structure that is absent from human cells, and is a potential target for antifungal treatments. Glucan is synthesized from the donor uridine diphosphate glucose, with the conversion of glucose-6-phosphate to glucose-1-phosphate by the enzyme phosphoglucomutase (PGM) representing a key step in its biosynthesis. Here, we explore the possibility of selectively targeting A. fumigatus PGM (AfPGM) as an antifungal treatment strategy. Using a promoter replacement strategy, we constructed a conditional pgm mutant and revealed that pgm is required for A. fumigatus growth and cell wall integrity. In addition, using a fragment screen, we identified the thiol-reactive compound ISFP1 (Isothiazolone Fragment of PGM) as targeting a cysteine residue not conserved in the human orthologue. Furthermore, through scaffold exploration, we synthesized a para-aryl derivative (ISFP10) and demonstrated that it inhibits AfPGM with an IC50 of 2 μM and exhibits 50-fold selectivity over the human enzyme. Taken together, our data provide genetic validation of PGM as a therapeutic target and suggest new avenues for inhibiting AfPGM using covalent inhibitors that could serve as tools for chemical validation.	Apr 2022

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I04-Macromolecular Crystallography

Genetic validation of Aspergillus fumigatus phosphoglucomutase as a viable therapeutic target in invasive aspergillosis

Kaizhou Yan , Mathew Stanley , Bartosz Kowalski , Olawale G. Raimi , Andrew T. Ferenbach , Pingzhen Wei , Wenxia Fang , Daniel M. F. Van Aalten

Journal Of Biological Chemistry 4

DOI: 10.1016/j.jbc.2022.102003

Diamond Proposal Number(s): [19844]