Inhibiting Fungal Echinocandin Resistance by Small-Molecule Disruption of Geranylgeranyltransferase Type I Activity

ABSTRACT

Echinocandin resistance in Candida is a great concern, as the echinocandin drugs are recommended as first-line therapy for patients with invasive candidiasis. However, therapeutic efforts to thwart echinocandin resistance have been hampered by a lack of fungal specific drug targets. Here, we show that deleting CDC43, the β subunit of geranylgeranyltransferase type I (GGTase I), confers hypersensitivity to echinocandins, which renders GGTase I a tractable target in combatting echinocandin resistance. The membrane localization of Rho1, which is critical for (1,3)-β-d-glucan synthase Fks1 activation, is disrupted in the cdc43 mutant, resulting in decreased amounts of glucans in the cell wall, thereby exacerbating the cell wall stress upon caspofungin addition. Guided by this insight, we found that selective chemical inhibition of GGTase I by L-269289 potentiates echinocandin activity and renders echinocandin-resistant Candida albicans responsive to treatment in vitro and in animal models for disseminated infection. Furthermore, L-269289 and echinocandins also act in a synergistic manner for the treatment of Candida tropicalis and Candida parapsilosis. Importantly, deletion of CDC43 is lethal in Candida glabrata. L-269289 is active on its own to kill C. glabrata, and its fungicidal activity is enhanced when combined with caspofungin. Thus, targeting GGTase I has therapeutic potential to address the clinical challenge of echinocandin-resistant candidiasis.