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

Stefanini, Irene; Rizzetto, Lisa; Rivero, Damariz; Carbonell, Silvia; Gut, Marta; Heath, Simon; Gut, Ivo Glynne; Trabocchi, Andrea; Guarna, Antonio; Ben Ghazzi, Nagwa; Bowyer, Paul; Kapushesky, Misha; Cavalieri, Duccio

doi:http://dx.doi.org/10.1038/s41598-018-24341-y

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

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Stefanini I, Rizzetto L, Rivero D, Carbonell S, Gut M, Heath S et al. Deciphering the mechanism of action of 089, a compound impairing the fungal cell cycle. Sci Rep. 2018;8(1):5964. DOI: 10.1038/s41598-018-24341-y

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.