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    How Antifungal Drugs Work: New Insights

    08/06/2018

    Researchers of the University of Würzburg were able to shed more light on the workings of a key antifungal agent. The current issue of the journal "Nature Communications" reports on their work.

    Hyphae of the human pathogenic fungus Aspergillus fumigatus after being exposed to azole. The fungal mitochondria are dyed red and the cell walls and cell wall patches are dyed black. The cell walls are so heavily damaged in some places that the mitochondria emerge. (Picture: J. Wagener)

    Aspergillus fumigatus is a species of fungus and the most common cause of severe and often lethal disease in individuals with an immunodeficiency, for example after a stem cell transplant or organ graft. Only a limited number of antifungal drugs are available for the treatment of "invasive aspergillosis". These drugs are, in a manner of speaking, the fungal counterpart of antibiotics. Scientists from the University of Würzburg were now able to figure out new details on the functioning of azoles, the most important class of antifungal agents presently available.

    Azoles work by inhibiting the synthesis of ergosterol. Ergosterol in fungal cells serves many of the same functions that cholesterol serves in human cells, acting like a kind of "plasticizer" at the cellular membrane. This is vital to keep the membrane flexible, mobile and resistant to protect the inside of the cell.

    First fungistatic, then fungicidal

    Azoles are known to either inhibit fungal growth or kill them, depending on the fungus species. Azole-based antifungal drugs usually have a fungistatic (growth inhibiting) effect on yeasts such as Candida albicans and a fungicidal (destroying) effect on A. fumigatus, for example.

    "We were able to show that azole antifungal agents initially also have a fungistatic effect on A. fumigatus," Dr. Johannes Wagener says; he is the lead author of the study published in the journal "Nature Communications". Only after several hours, is a "cell wall stress signalling pathway" activated which results in uncontrolled synthesis of fungal cell wall. "Invaginations are created, the so-called "patches"; the cell is under stress which ultimately results in cell lysis: The cell dies," Wagener explains.

    Early detection of resistance possible

    "This additional fungicidal effect depends on the fungus' respiratory chain and can be mitigated by simultaneously inhibiting cell wall synthesis," Wagener goes on. The excessive synthesis of cell wall is visible under the microscope and could hence be used in the future to detect azole resistance at an early stage.

    "The effects of azole antifungal agents on the synthesis and integrity of the cell wall were totally unexpected for us," Wagener says; he works at the Department of Medical Microbiology & Mycology with Professor Oliver Kurzai. There are other antifungal agents that target the cell walls. "So we now have two completely different classes of antifungal agents that act in totally different ways which can now be contextualized in an unexpected manner," Wagener says.

    "Moreover, we were able to show that the azole-induced cell wall synthesis does not occur in azole-resistant Aspergillus isolates," Wagener continues. Azole resistance is a serious problem in certain regions such as the Netherlands. Azole-induced cell wall synthesis could hence be used to distinguish azole-resistant from azole-sensitive Aspergillus isolates.

    "The work is interesting because it not only delivers new approaches to explain the different effects of these drugs on different fungus species, it might also provide the basis for new treatment strategies or new methods of resistance testing," says chair holder, Professor Oliver Kurzai.

    The current findings of Wagener and Kurzai raise other questions that need to be answered: "We have to continue our efforts to determine how exactly these agents work. One question is, for example: Why do azoles create patches?"

     

    "Azole-induced cell wall carbohydrate patches kill Aspergillus fumigatus" by Wagener et al.

    Published by Nature Communications.

    DOI: https://www.doi.org/10.1038/s41467-018-05497-7

    Contact

    Dr. Johannes Wagener, MD, Specialist in Microbiology, Virology and Infectious Epidemiology, Institute for Hygiene and Microbiology, Phone: +49-(0)931-31-84941, e-mail: j.wagener@hygiene.uni-wuerzburg.de

     

    By Marco Bosch

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