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Deciphering the mechanism of action of 089, a compound impairing the fungal cell cycle

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Stefanini, Irene, Rizzetto, Lisa, Rivero, Damariz, Carbonell, Silvia, Gut, Marta, Heath, Simon, Gut, Ivo G, Trabocchi, Andrea, Guarna, Antonio, Ben Ghazzi, Nagwa, Bowyer, Paul, Kapushesky, Misha and Cavalieri, Duccio (2018) Deciphering the mechanism of action of 089, a compound impairing the fungal cell cycle. Scientific Reports, 8 (1). 5964. doi:10.1038/s41598-018-24341-y ISSN 2045-2322.

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Official URL: https://doi.org/10.1038/s41598-018-24341-y

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Abstract

Fungal infections represent an increasingly relevant clinical problem, primarily because of the increased survival of severely immune-compromised patients. Despite the availability of active and selective drugs and of well-established prophylaxis, classical antifungals are often ineffective as resistance is frequently observed. The quest for anti-fungal drugs with novel mechanisms of action is thus important. Here we show that a new compound, 089, acts by arresting fungal cells in the G2 phase of the cell cycle through targeting of SWE1, a mechanism of action unexploited by current anti-fungal drugs. The cell cycle impairment also induces a modification of fungal cell morphology which makes fungal cells recognizable by immune cells. This new class of molecules holds promise to be a valuable source of novel antifungals, allowing the clearance of pathogenic fungi by both direct killing of the fungus and enhancing the recognition of the pathogen by the host immune system.

Item Type: Journal Article
Subjects: R Medicine > RM Therapeutics. Pharmacology
R Medicine > RS Pharmacy and materia medica
Divisions: Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Cell & Developmental Biology
Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences
Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School
SWORD Depositor: Library Publications Router
Library of Congress Subject Headings (LCSH): Antifungal agents, Skin -- Infections -- Treatment
Journal or Publication Title: Scientific Reports
Publisher: Nature Publishing Group
ISSN: 2045-2322
Official Date: 13 April 2018
Dates:
DateEvent
13 April 2018Published
29 April 2018Accepted
Volume: 8
Number: 1
Article Number: 5964
DOI: 10.1038/s41598-018-24341-y
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access (Creative Commons)
Date of first compliant deposit: 3 May 2018
Date of first compliant Open Access: 4 May 2018
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
HEALTH-2010-242220 “SYBARIS”Seventh Framework Programmehttp://dx.doi.org/10.13039/100011102
[242220]-JPI ENPADASISeventh Framework Programmehttp://dx.doi.org/10.13039/100011102
Institutional Strategic Support Fund: 105627/Z/14/ZUniversity of Warwickhttp://dx.doi.org/10.13039/501100000741

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