{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:43:06Z","timestamp":1788914586168,"version":"build-2803163510"},"reference-count":59,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2023,8,31]],"date-time":"2023-08-31T00:00:00Z","timestamp":1693440000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Dim1Health Ile-de-France"},{"name":"Dim1Health Ile-de-France"},{"DOI":"10.13039\/100007631","name":"CIFAR","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100007631","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Fungal infections are rising, with over 1.5 billion cases and more than 1 million deaths recorded each year. Among these,\n                    <jats:italic>Candida<\/jats:italic>\n                    infections are frequent in at-risk populations and the rapid development of drug resistance and tolerance contributes to their clinical persistence. Few antifungal drugs are available, and their efficacy is declining due to the environmental overuse and the expansion of multidrug-resistant species. One way to prolong their utility is by applying them in combination therapy. Here, we highlight recently described azole potentiators belonging to different categories: natural, repurposed, or novel compounds. We showcase examples of molecules and discuss their identified or proposed mode of action. We also emphasise the challenges in azole potentiator development, compounded by the lack of animal testing, the overreliance on\n                    <jats:italic>Candida albicans<\/jats:italic>\n                    and\n                    <jats:italic>Candida auris<\/jats:italic>\n                    , as well as the limited understanding of compound efficacy.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1011583","type":"journal-article","created":{"date-parts":[[2023,8,31]],"date-time":"2023-08-31T13:23:14Z","timestamp":1693488194000},"page":"e1011583","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":20,"title":["Azole potentiation in Candida species"],"prefix":"10.1371","volume":"19","author":[{"given":"Jan S.","family":"Stenkiewicz-Witeska","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1136-8471","authenticated-orcid":true,"given":"Iuliana V.","family":"Ene","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,8,31]]},"reference":[{"issue":"2","key":"ppat.1011583.ref001","doi-asserted-by":"crossref","first-page":"e74","DOI":"10.1016\/S2666-5247(23)00003-4","article-title":"WHO publish fungal priority pathogens list","volume":"4","author":"T. Burki","year":"2023","journal-title":"Lancet Microbe"},{"issue":"1","key":"ppat.1011583.ref002","doi-asserted-by":"crossref","first-page":"5352","DOI":"10.1038\/s41467-022-32249-5","article-title":"The importance of antimicrobial resistance in medical mycology","volume":"13","author":"NAR Gow","year":"2022","journal-title":"Nat Commun"},{"key":"ppat.1011583.ref003","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1146\/annurev-micro-030117-020345","article-title":"Molecular Evolution of Antifungal Drug Resistance","volume":"71","author":"N Robbins","year":"2017","journal-title":"Annu Rev Microbiol"},{"issue":"9","key":"ppat.1011583.ref004","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/s41579-022-00720-1","article-title":"Tackling the emerging threat of antifungal resistance to human health","volume":"20","author":"MC Fisher","year":"2022","journal-title":"Nat Rev 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Chest"},{"issue":"49","key":"ppat.1011583.ref008","doi-asserted-by":"crossref","first-page":"4255","DOI":"10.1016\/S0040-4039(01)88668-8","article-title":"The structure of beauvericin, a new depsipeptide antibiotic toxic to artemia salina","volume":"10","author":"RL Hamill","year":"1969","journal-title":"Tetrahedron Lett"},{"issue":"11","key":"ppat.1011583.ref009","doi-asserted-by":"crossref","first-page":"4606","DOI":"10.1073\/pnas.0609370104","article-title":"High-throughput synergy screening identifies microbial metabolites as combination agents for the treatment of fungal infections","volume":"104","author":"L Zhang","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"5744","key":"ppat.1011583.ref010","doi-asserted-by":"crossref","first-page":"2185","DOI":"10.1126\/science.1118370","article-title":"Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi","volume":"309","author":"LE Cowen","year":"2005","journal-title":"Science"},{"issue":"10","key":"ppat.1011583.ref011","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1038\/nchembio.2165","article-title":"Dual action antifungal small molecule modulates multidrug efflux and TOR signaling","volume":"12","author":"T Shekhar-Guturja","year":"2016","journal-title":"Nat Chem Biol"},{"issue":"9","key":"ppat.1011583.ref012","first-page":"1041","article-title":"Cyclosporin A: a powerful immunosuppressant","volume":"126","author":"A Laupacis","year":"1982","journal-title":"Can Med Assoc J"},{"issue":"4","key":"ppat.1011583.ref013","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1093\/emboj\/21.4.546","article-title":"Calcineurin is essential for survival during membrane stress in Candida albicans","volume":"21","author":"MC Cruz","year":"2002","journal-title":"EMBO 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NY)"},{"issue":"5","key":"ppat.1011583.ref020","doi-asserted-by":"crossref","DOI":"10.1172\/JCI145123","article-title":"Turbinmicin inhibits Candida biofilm growth by disrupting fungal vesicle\u2013mediated trafficking","volume":"131","author":"M Zhao","year":"2021","journal-title":"J Clin Invest"},{"issue":"1","key":"ppat.1011583.ref021","doi-asserted-by":"crossref","first-page":"3634","DOI":"10.1038\/s41467-022-31308-1","article-title":"Targeting fungal membrane homeostasis with imidazopyrazoindoles impairs azole resistance and biofilm formation","volume":"13","author":"NM Revie","year":"2022","journal-title":"Nat Commun"},{"issue":"2","key":"ppat.1011583.ref022","doi-asserted-by":"crossref","DOI":"10.3390\/pathogens7020056","article-title":"Antifungal Activity and Synergism with Azoles of Polish Propolis","volume":"7","author":"K 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Nosengo","year":"2016","journal-title":"Nature"},{"issue":"2","key":"ppat.1011583.ref034","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1080\/14756360500533059","article-title":"Antibacterial, antifungal and cytotoxic properties of some sulfonamide-derived chromones","volume":"21","author":"ZH Chohan","year":"2006","journal-title":"J Enzyme Inhib Med Chem"},{"issue":"3","key":"ppat.1011583.ref035","doi-asserted-by":"crossref","first-page":"e00701","DOI":"10.1128\/AAC.00701-17","article-title":"Reversal of Azole Resistance in Candida albicans by Sulfa Antibacterial Drugs","volume":"62","author":"HE Eldesouky","year":"2018","journal-title":"Antimicrob Agents Chemother"},{"issue":"6","key":"ppat.1011583.ref036","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1016\/j.ijantimicag.2018.08.016","article-title":"Synergistic interactions of sulfamethoxazole and azole antifungal drugs against emerging multidrug-resistant Candida auris","volume":"52","author":"HE Eldesouky","year":"2018","journal-title":"Int J Antimicrob Agents"},{"issue":"6","key":"ppat.1011583.ref037","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1016\/j.ijantimicag.2006.07.012","article-title":"Antifolates as antimycotics?: Connection between the folic acid cycle and the ergosterol biosynthesis pathway in Candida albicans","volume":"28","author":"MD Navarro-Mart\u00ednez","year":"2006","journal-title":"Int J Antimicrob Agents"},{"issue":"1","key":"ppat.1011583.ref038","doi-asserted-by":"crossref","DOI":"10.1128\/AAC.00684-20","article-title":"Potent Synergistic Interactions between Lopinavir and Azole Antifungal Drugs against Emerging Multidrug-Resistant Candida auris","volume":"65","author":"HE Eldesouky","year":"2020","journal-title":"Antimicrob Agents Chemother"},{"issue":"11","key":"ppat.1011583.ref039","doi-asserted-by":"crossref","first-page":"5379","DOI":"10.3390\/cimb44110364","article-title":"Repurposing HIV Protease Inhibitors Atazanavir and Darunavir as Antifungal Treatments against Candida albicans Infections: An In Vitro and In Vivo Study","volume":"44","author":"JC Fenley","year":"2022","journal-title":"Curr Issues Mol Biol"},{"issue":"5","key":"ppat.1011583.ref040","doi-asserted-by":"crossref","first-page":"e01631","DOI":"10.1128\/aac.01631-22","article-title":"Atazanavir Resensitizes Candida auris to Azoles","volume":"67","author":"Y Elgammal","year":"2023","journal-title":"Antimicrob Agents Chemother"},{"issue":"1","key":"ppat.1011583.ref041","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1080\/21505594.2020.1838741","article-title":"Aprepitant, an antiemetic agent, interferes with metal ion homeostasis of Candida auris and displays potent synergistic interactions with azole drugs","volume":"11","author":"HE Eldesouky","year":"2020","journal-title":"Virulence"},{"issue":"1","key":"ppat.1011583.ref042","doi-asserted-by":"crossref","first-page":"6089","DOI":"10.1038\/s41598-020-62976-y","article-title":"Ospemifene displays broad-spectrum synergistic interactions with itraconazole through potent interference with fungal efflux activities","volume":"10","author":"HE Eldesouky","year":"2020","journal-title":"Sci Rep"},{"issue":"1","key":"ppat.1011583.ref043","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1038\/s41598-019-57174-4","article-title":"Proton pump inhibitors act synergistically with fluconazole against resistant Candida albicans","volume":"10","author":"M Lu","year":"2020","journal-title":"Sci Rep"},{"key":"ppat.1011583.ref044","doi-asserted-by":"crossref","first-page":"107483","DOI":"10.1016\/j.pharmthera.2020.107483","article-title":"Antifungal effects of statins","volume":"208","author":"A Tavakkoli","year":"2020","journal-title":"Pharmacol Ther"},{"issue":"1","key":"ppat.1011583.ref045","doi-asserted-by":"crossref","first-page":"7525","DOI":"10.1038\/s41598-020-64571-7","article-title":"Repurposing approach identifies pitavastatin as a potent azole chemosensitizing agent effective against azole-resistant Candida species","volume":"10","author":"HE Eldesouky","year":"2020","journal-title":"Sci Rep"},{"key":"ppat.1011583.ref046","doi-asserted-by":"crossref","first-page":"e54160","DOI":"10.7554\/eLife.54160","article-title":"Synergistic and antagonistic drug interactions in the treatment of systemic fungal infections","volume":"9","author":"MA Wambaugh","year":"2020","journal-title":"Elife"},{"key":"ppat.1011583.ref047","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.ejmech.2017.07.030","article-title":"Repurposing antipsychotic drugs into antifungal agents: Synergistic combinations of azoles and bromperidol derivatives in the treatment of various fungal infections","volume":"139","author":"SYL Holbrook","year":"2017","journal-title":"Eur J Med Chem"},{"issue":"5","key":"ppat.1011583.ref048","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1021\/acsinfecdis.9b00197","article-title":"Drug Repurposing of Haloperidol: Discovery of New Benzocyclane Derivatives as Potent Antifungal Agents against Cryptococcosis and Candidiasis","volume":"6","author":"C Ji","year":"2020","journal-title":"ACS Infectious Diseases"},{"issue":"10","key":"ppat.1011583.ref049","doi-asserted-by":"crossref","first-page":"6179","DOI":"10.1128\/AAC.03046-15","article-title":"The Synergistic Effect of Azoles and Fluoxetine against Resistant Candida albicans Strains Is Attributed to Attenuating Fungal Virulence","volume":"60","author":"W Gu","year":"2016","journal-title":"Antimicrob Agents Chemother"},{"issue":"3","key":"ppat.1011583.ref050","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1128\/AAC.05706-11","article-title":"The monoamine oxidase A inhibitor clorgyline is a broad-spectrum inhibitor of fungal ABC and MFS transporter efflux pump activities which reverses the azole resistance of Candida albicans and Candida glabrata clinical isolates","volume":"56","author":"AR Holmes","year":"2012","journal-title":"Antimicrob Agents 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Alabi","year":"2023","journal-title":"MBio"},{"issue":"1","key":"ppat.1011583.ref054","doi-asserted-by":"crossref","first-page":"106820","DOI":"10.1016\/j.ijantimicag.2023.106820","article-title":"Small molecule II-6s synergises with fluconazole against Candida albicans","volume":"62","author":"S Yang","year":"2023","journal-title":"Int J Antimicrob Agents"},{"issue":"5","key":"ppat.1011583.ref055","doi-asserted-by":"crossref","DOI":"10.1128\/AAC.01998-18","article-title":"Inhibition of Vesicular Transport Influences Fungal Susceptibility to Fluconazole","volume":"63","author":"L Demuyser","year":"2019","journal-title":"Antimicrob Agents Chemother"},{"issue":"25","key":"ppat.1011583.ref056","doi-asserted-by":"crossref","first-page":"9497","DOI":"10.1073\/pnas.0402121101","article-title":"Sorting inhibitors (Sortins): Chemical compounds to study vacuolar sorting in Arabidopsis","volume":"101","author":"J Zouhar","year":"2004","journal-title":"Proc Natl Acad Sci U S 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