Evidence that G-quadruplexes form in pathogenic fungi and represent promising antifungal targets

Middleton, Georgie, Mahamud, Fuad O., Storer, Isabelle S. R., Williams-Gunn, Abigail, Wostear, Finn, Abdolrasouli, Alireza, Barclay, Elaine, Bradford, Alice, Steward, Oliver, Schelenz, Silke, McColl, James, Lézé, Bertrand, van Rhijn, Norman, da Silva Dantas, Alessandra, Furukawa, Takanori, Warren, Derek, Waller, Zoë A. E. and Bidula, Stefan (2025) Evidence that G-quadruplexes form in pathogenic fungi and represent promising antifungal targets. EMBO Molecular Medicine. ISSN 1757-4676

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Abstract

Fungi are estimated to cause the death of almost 4 million people annually, and we urgently need new drug targets to overcome antifungal resistance. We found that four-stranded nucleic acid structures called G-quadruplexes (G4s) could form within the critical priority fungal pathogen Aspergillus fumigatus. Sequences with the potential to form G4s could be found in genes involved in fungal growth, virulence, and drug resistance. This included cyp51A, which encodes the target of azoles. Notably, we observed the formation of both canonical and unusual acid-stabilised G4s in these sequences. We found that PhenDC3 (a G4-stabilising ligand) could refold DNA into antiparallel G4 structures in cyp51A that were associated with decreased transcription. PhenDC3 also had potent fungistatic activity, prevented germination, synergised with the antifungal amphotericin B in vitro and in vivo, and displayed low genotoxicity and cytotoxicity towards human cells. Interestingly, PhenDC3 had greater antifungal activity towards the pan-azole-resistant A. fumigatus TR34/L98H isolate, and another G4-stabiliser, pyridostatin, killed multi-drug-resistant Candida auris. Taken together, G4s represent a promising target for the development of antifungals with novel mechanisms of action.

Item Type:	Article
Additional Information:	Data availability: The source data of this paper are collected in the following database record https://doi.org/10.5281/zenodo.17192248. The source data of this paper are collected in the following database record: biostudies:S-SCDT-10_1038-S44321-025-00340-1. Funding: This work was supported by the Academy of Medical Sciences [SBF008\1046 to SB] and [SBF0010\1140 to TF], British Mycological Society to TF, Biotechnology and Biological Sciences Research Council [BB/Y005058/1 to SB; BB/W001616/1 to ZAEW], Wellcome Trust [226408/Z/22/Z to NvR], Royal Society Research Grant [RG\R2\232363] and the NIHR Newcastle Biomedical Research Centre (BRC) to AdSD, and Thomas Marns Scholarship to FOM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Faculty \ School:	Faculty of Science > School of Chemistry, Pharmacy and Pharmacology Faculty of Science Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups:	Faculty of Science > Research Groups > Molecular and Tissue Pharmacology Faculty of Medicine and Health Sciences > Research Groups > Pathogen Biology Group
Related URLs:	https://www.embopress.org/doi/full/10.10...
Depositing User:	LivePure Connector
Date Deposited:	17 Nov 2025 17:30
Last Modified:	17 Nov 2025 17:30
URI:	https://ueaeprints.uea.ac.uk/id/eprint/101052
DOI:	10.1038/s44321-025-00340-1

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