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Here, we identify, through a genetic screen, the vacuolar membrane\u2010resident phosphatidylinositol 3\u2010phosphate 5\u2010kinase (CgFab1) to be a novel determinant of azole tolerance. We demonstrate for the first time that fluconazole promotes actin cytoskeleton reorganization in the emerging, inherently less azole\u2010susceptible fungal pathogen <jats:italic>Candida glabrata<\/jats:italic>, and genetic or chemical perturbation of actin structures results in intracellular sterol accumulation and azole susceptibility. Further, <jats:italic>CgFAB1<\/jats:italic> disruption impaired vacuole homeostasis and actin organization, and the F\u2010actin\u2010stabilizing compound jasplakinolide rescued azole toxicity in cytoskeleton defective\u2010mutants including the <jats:italic>Cgfab1\u0394<\/jats:italic> mutant. In vitro assays revealed that the actin depolymerization factor CgCof1 binds to multiple lipids including phosphatidylinositol 3,5\u2010bisphosphate. Consistently, CgCof1 distribution along with the actin filament\u2010capping protein CgCap2 was altered upon both <jats:italic>CgFAB1<\/jats:italic> disruption and fluconazole exposure. Altogether, these data implicate CgFab1 in azole tolerance through actin network remodeling. Finally, we also show that actin polymerization inhibition rendered fluconazole fully and partially fungicidal in azole\u2010susceptible and azole\u2010resistant <jats:italic>C. glabrata<\/jats:italic> clinical isolates, respectively, thereby, underscoring the role of fluconazole\u2010effectuated actin remodeling in azole resistance.<\/jats:p>","DOI":"10.1111\/mmi.14110","type":"journal-article","created":{"date-parts":[[2018,8,23]],"date-time":"2018-08-23T15:23:45Z","timestamp":1535037825000},"page":"425-443","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Fluconazole\u2010induced actin cytoskeleton remodeling requires phosphatidylinositol 3\u2010phosphate 5\u2010kinase in the pathogenic yeast <i>Candida glabrata<\/i>"],"prefix":"10.1111","volume":"110","author":[{"given":"Priyanka","family":"Bhakt","sequence":"first","affiliation":[{"name":"Laboratory of Fungal Pathogenesis Centre for DNA Fingerprinting and 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