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The bottommost layers of biofilms experience nutrient limitation where\n                    <jats:italic>C<\/jats:italic>\n                    .\n                    <jats:italic>albicans<\/jats:italic>\n                    cells are required to respire. We previously reported that a protein Ndu1 is essential for\n                    <jats:italic>Candida<\/jats:italic>\n                    mitochondrial respiration; loss of\n                    <jats:italic>NDU1<\/jats:italic>\n                    causes inability of\n                    <jats:italic>C<\/jats:italic>\n                    .\n                    <jats:italic>albicans<\/jats:italic>\n                    to grow on alternative carbon sources and triggers early biofilm detachment. Here, we screened a repurposed library of FDA-approved small molecule inhibitors to identify those that prevent NDU1-associated functions. We identified an antihelminthic drug, Niclosamide (NCL), which not only prevented growth on acetate,\n                    <jats:italic>C<\/jats:italic>\n                    .\n                    <jats:italic>albicans<\/jats:italic>\n                    hyphenation and early biofilm growth, but also completely disengaged fully grown biofilms of drug-resistant\n                    <jats:italic>C<\/jats:italic>\n                    .\n                    <jats:italic>albicans<\/jats:italic>\n                    and\n                    <jats:italic>Candida auris<\/jats:italic>\n                    from their growth surface. To overcome the suboptimal solubility and permeability of NCL that is well known to affect its in vivo efficacy, we developed NCL-encapsulated Eudragit EPO (an FDA-approved polymer) nanoparticles (NCL-EPO-NPs) with high niclosamide loading, which also provided long-term stability. The developed NCL-EPO-NPs completely penetrated mature biofilms and attained anti-biofilm activity at low microgram concentrations. NCL-EPO-NPs induced ROS activity in\n                    <jats:italic>C<\/jats:italic>\n                    .\n                    <jats:italic>albicans<\/jats:italic>\n                    and drastically reduced oxygen consumption rate in the fungus, similar to that seen in an NDU1 mutant. NCL-EPO-NPs also significantly abrogated mucocutaneous candidiasis by fluconazole-resistant strains of\n                    <jats:italic>C<\/jats:italic>\n                    .\n                    <jats:italic>albicans<\/jats:italic>\n                    , in mice models of oropharyngeal and vulvovaginal candidiasis. To our knowledge, this is the first study that targets biofilm detachment as a target to get rid of drug-resistant\n                    <jats:italic>Candida<\/jats:italic>\n                    biofilms and uses NPs of an FDA-approved nontoxic drug to improve biofilm penetrability and microbial killing.\n                  <\/jats:p>","DOI":"10.1371\/journal.pbio.3001762","type":"journal-article","created":{"date-parts":[[2022,8,17]],"date-time":"2022-08-17T13:30:08Z","timestamp":1660743008000},"page":"e3001762","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":31,"title":["Niclosamide-loaded nanoparticles disrupt Candida biofilms and protect mice from mucosal candidiasis"],"prefix":"10.1371","volume":"20","author":[{"given":"Yogesh","family":"Sutar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunna","family":"Nabeela","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shakti","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdullah","family":"Alqarihi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norma","family":"Solis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teklegiorgis","family":"Ghebremariam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Filler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashraf S.","family":"Ibrahim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhijit","family":"Date","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5889-054X","authenticated-orcid":true,"given":"Priya","family":"Uppuluri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,8,17]]},"reference":[{"key":"pbio.3001762.ref001","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1086\/421946","article-title":"Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study","volume":"39","author":"H Wisplinghoff","year":"2004","journal-title":"Clin Infect Dis"},{"key":"pbio.3001762.ref002","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.ijantimicag.2013.09.005","article-title":"Nosocomial bloodstream infections due to Candida spp. in the USA: species distribution, clinical features and antifungal susceptibilities","volume":"43","author":"H Wisplinghoff","year":"2014","journal-title":"Int J Antimicrob Agents"},{"key":"pbio.3001762.ref003","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1097\/01.inf.0000078159.53132.40","article-title":"Nosocomial bloodstream infections in pediatric patients in United States hospitals: epidemiology, clinical features and susceptibilities","volume":"22","author":"H Wisplinghoff","year":"2003","journal-title":"Pediatr Infect Dis J"},{"key":"pbio.3001762.ref004","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1086\/374339","article-title":"Current trends in the epidemiology of nosocomial bloodstream infections in patients with hematological malignancies and solid neoplasms in hospitals in the United States","volume":"36","author":"H Wisplinghoff","year":"2003","journal-title":"Clin Infect Dis"},{"key":"pbio.3001762.ref005","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1086\/378745","article-title":"Attributable mortality of nosocomial candidemia, revisited","volume":"37","author":"O Gudlaugsson","year":"2003","journal-title":"Clin Infect Dis"},{"key":"pbio.3001762.ref006","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1007\/s11908-005-0044-7","article-title":"Global trends in candidemia: review of reports from 1995\u20132005","volume":"7","author":"J. 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