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

DOI: 10.1016/j.jbc.2022.102003 DOI Help

Authors: Kaizhou Yan (University of Dundee) , Mathew Stanley (University of Dundee) , Bartosz Kowalski (University of Dundee) , Olawale G. Raimi (University of Dundee) , Andrew T. Ferenbach (University of Dundee) , Pingzhen Wei (National Engineering Research Center for Non-Food Biorefinery, Guangxi Academy of Sciences) , Wenxia Fang (National Engineering Research Center for Non-Food Biorefinery, Guangxi Academy of Sciences,) , Daniel M. F. Van Aalten (University of Dundee)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Biological Chemistry , VOL 4

State: Published (Approved)
Published: April 2022
Diamond Proposal Number(s): 19844

Open Access Open Access

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.

Diamond Keywords: Fungi

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I04-Macromolecular Crystallography

Other Facilities: ESRF

Added On: 04/05/2022 09:55


Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Biochemistry Genetics Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)