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However, the fungistatic nature of FLC renders pathogenic fungi capable of developing tolerance towards it. Consequently, converting FLC into a fungicidal agent using adjuvants assumes significance to circumvent FLC resistance and the perpetuation of fungal infections. This drug repurposing study has successfully identified pitavastatin calcium (PIT) as a promising adjuvant for enhancing the fungicidal activity of FLC from a comprehensive library of 2372 FDA-approved drugs. PIT could render FLC fungicidal even at concentrations as low as 1 \u03bcM. The median lethal dose (LD50) of PIT was determined to be 103.6 mg\/kg. We have discovered that PIT achieves its synergistic effect by inhibiting the activity of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, thereby impeding ubiquinone biosynthesis, inducing reactive oxygen species (ROS) generation, triggering apoptosis, and disrupting Golgi function. We employed a Candida albicans strain that demonstrated a notable tolerance to FLC to infect mice and found that PIT effectively augmented the antifungal efficacy of FLC against IFIs. This study is an illustrative example of how FDA-approved drugs can effectively eliminate fungal tolerance to FLC.<\/jats:p>","DOI":"10.3390\/antiox13060667","type":"journal-article","created":{"date-parts":[[2024,5,31]],"date-time":"2024-05-31T06:35:32Z","timestamp":1717137332000},"page":"667","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Pitavastatin Calcium Confers Fungicidal Properties to Fluconazole by Inhibiting Ubiquinone Biosynthesis and Generating Reactive Oxygen Species"],"prefix":"10.3390","volume":"13","author":[{"given":"Wanqian","family":"Li","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Shanghai Tenth People\u2019s Hospital, School of Medicine, Tongji University, Shanghai 200072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanru","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Shanghai Tenth People\u2019s Hospital, School of Medicine, Tongji University, Shanghai 200072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Shanghai Tenth People\u2019s Hospital, School of Medicine, Tongji University, Shanghai 200072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Shanghai Tenth People\u2019s Hospital, School of Medicine, Tongji University, Shanghai 200072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6619-7983","authenticated-orcid":false,"given":"Malcolm","family":"Whiteway","sequence":"additional","affiliation":[{"name":"Department of Biology, Concordia University, Montreal, QC H4B 1R6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8422-0427","authenticated-orcid":false,"given":"Hui","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Shanghai Tenth People\u2019s Hospital, School of Medicine, Tongji University, Shanghai 200072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanying","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Shanghai Tenth People\u2019s Hospital, School of Medicine, Tongji University, Shanghai 200072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"114960","DOI":"10.1016\/j.addr.2023.114960","article-title":"Candidiasis: From cutaneous to systemic, new perspectives of potential targets and therapeutic strategies","volume":"199","author":"Lu","year":"2023","journal-title":"Adv. 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