Gladiolin produced by pathogenic <i>Burkholderia</i> synergizes with amphotericin B through membrane lipid rearrangements
Amphotericin B (AmpB) is one of the oldest antifungal drugs in clinical use. It is an effective therapeutic, but it comes with toxicity issues due to the similarities between its fungal target (the membrane lipid ergosterol) and its mammalian counterpart (cholesterol). One strategy to improve its activity/toxicity relationship is by combinatorial therapy with potentiators, which would enable a lower therapeutic dose of AmpB. Here, we report on the discovery of the antibiotic gladiolin as a potentiator of AmpB against several priority human fungal pathogens and fungal biofilms, with no increased toxicity against mammalian cells. We show that gladiolin potentiates AmpB by increasing and accelerating membrane damage. Our findings also provide insights into the on-going debate about the mechanism of action of AmpB by indicating that both proposed mechanisms, extraction of ergosterol from membranes and pore formation, are potentiated by gladiolin.
Authors
- Tzong-Hsien Lee
- Dean Walsh (ORCID: https://orcid.org/0009-0009-9840-1673)
- Harshini Weerasinghe (ORCID: https://orcid.org/0000-0003-2680-1108)
- Claudia Simm (ORCID: https://orcid.org/0000-0002-1747-0418)
- Freya Harrison (ORCID: https://orcid.org/0000-0002-5743-5078)
- Marie‐Isabel Aguilar
- Wai Chung Tse (ORCID: https://orcid.org/0000-0002-2068-883X)
- Madhu Shankar (ORCID: https://orcid.org/0000-0002-3553-135X)
- Ioanna T. Nakou
- Roger J. Mulder (ORCID: https://orcid.org/0000-0002-8740-802X)
- Ana Traven (ORCID: https://orcid.org/0000-0001-6252-3104)
- Gregory L. Challis (ORCID: https://orcid.org/0000-0001-5976-3545)
- Ross B. Inman
- Yu Zhang (ORCID: https://orcid.org/0000-0001-8296-154X)
Institutions
- University of Exeter (GB)
- Australian Regenerative Medicine Institute (AU)
- University of Warwick (GB)
- ARC Centre of Excellence for Innovations in Peptide and Protein Science (AU)
- CSIRO Manufacturing (AU)
- Monash University (AU)
- Medical Research Council (GB)
Publication Details
- Journal
- mBio
- Published
- 2024-10-18
- DOI
- https://doi.org/10.1128/mbio.02611-24
- Citations
- 3
- Primary Topic
- Antifungal resistance and susceptibility
- Type
- article
- Field-Weighted Citation Impact
- 1.17
Funders
- National Institute for Health and Care Research
- University of Exeter
- University of Warwick
- Medical Research Council Centre for Medical Mycology
- Centers for Disease Control and Prevention
- Medical Research Council
- Biotechnology and Biological Sciences Research Council
- National Health and Medical Research Council