Deciphering the mechanism of action of 089, a compound impairing the fungal cell cycle
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. ; This project was supported by European Union's Seventh Framework Programme [FP7/2007-2013] under grant agreement n° HEALTH-2010-242220 ("SYBARIS") and by EU Framework Programme 7 Collaborative Project [242220]-JPI ENPADASI. I.S. was supported by the "Sybaris" project and by a fellowship from the Wellcome Warwick Quantitative Biomedicine Programme (Institutional Strategic Support Fund: 105627/Z/14/Z). The authors would like to thank Enrica Calura and Gavin Sherlock for support and critical comments on the analyses.
