{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,8]],"date-time":"2025-11-08T22:59:54Z","timestamp":1762642794540,"version":"3.41.2"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,12,9]],"date-time":"2022-12-09T00:00:00Z","timestamp":1670544000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004731","name":"Natural Science Foundation of Zhejiang Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Cryptococcosis is a global invasive mycosis with high rates of morbidity and mortality, especially in AIDS patients. Its treatment remains challenging because of the limited antifungals and their unavoidable toxicity, and as such more efforts need to focus on the development of novel effective drugs. Previous studies have indicated that pyrvinium pamoate (PP) has individual and synergistic fungistatic effect. In this study, the effects of PP alone and in combination with azoles [fluconazole (FLU), itraconazole (ITR), voriconazole (VOR), posaconazole (POS)] or amphotericin B (AmB) were evaluated against <jats:italic>Cryptococcus neoformans<\/jats:italic> both <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A total of 20 <jats:italic>C. neoformans<\/jats:italic> strains collected from cryptococcal pneumonia and cryptococcal meningitis were studied. The effects of PP alone, PP-azoles and PP-AmB interactions against <jats:italic>C. neoformans<\/jats:italic> were evaluated <jats:italic>via<\/jats:italic> the microdilution chequerboard technique, adapted from broth microdilution method according to the CLSI M27-A4. The <jats:italic>in vivo<\/jats:italic> antifungal activity of PP alone and in combination with azoles and AmB against <jats:italic>C. neoformans<\/jats:italic> infections was evaluated by <jats:italic>Galleria mellonella<\/jats:italic> survival assay.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The <jats:italic>in vitro<\/jats:italic> results revealed that PP individually was ineffective against <jats:italic>C. neoformans<\/jats:italic> (MIC&amp;gt;16 \u03bcg\/ml). Nevertheless, the synergistic effects of PP with ITR, VOR, POS, FLU or AmB was observed in 13 (65.0%, FICI 0.188\u20130.365), 3 (15.0%, FICI 0.245-0.301), 19 (95.0%, FICI 0.188-0.375), 7 (35.0%, FICI 0.188-0.375), and 12(60.0%, FICI 0.281-0.375) strains of <jats:italic>C. neoformans<\/jats:italic>, respectively. There was no antagonism. The survival rates of larvae treated with PP (3.33%) showed almost no antifungal effective, but the larvae survival rates improved when PP combined with AmB (35% vs. 23.33%), FLU (40% vs. 25%), ITR (48.33% vs. 33.33%), VOR (48.33% vs. 53.33%) and POS (56.67% vs. 36.67%) comparison with AmB or azoles alone, and statistical significance was observed when PP combined with POS versus POS alone (<jats:italic>P<\/jats:italic> = 0.04). <\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In summary, the preliminary results indicated the potential of PP in reduction the MICs of azoles and AmB, also itself against <jats:italic>C. neoformans<\/jats:italic>; the combination of PP with AMB, FLU, ITR, VOR and POS improve the survival rates of <jats:italic>C. neoformans<\/jats:italic> infection larvae, compared with they are alone. The <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> data show that PP could enhance the activity of POS against <jats:italic>C. neoformans.<\/jats:italic> This study contributes with data of PP in combination with classical drugs of choice for cryptococcosis treatment.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcimb.2022.1074903","type":"journal-article","created":{"date-parts":[[2022,12,9]],"date-time":"2022-12-09T06:09:15Z","timestamp":1670566155000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Synergistic effect of pyrvinium pamoate and posaconazole against Cryptococcus neoformans in vitro and in vivo"],"prefix":"10.3389","volume":"12","author":[{"given":"Yali","family":"Li","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sheng","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jialing","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Fang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,12,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics9120877","article-title":"Drug-resistant fungi: an emerging challenge threatening our limited antifungal armamentarium","volume":"9","author":"Arastehfar","year":"2020","journal-title":"Antibiotics (Basel)"},{"key":"B2","doi-asserted-by":"publisher","first-page":"349","DOI":"10.4269\/ajtmh.1959.8.349","article-title":"The treatment of pinworm infections in humans (enterobiasis) with pyrvinium chloride and pyrvinium pamoate","volume":"8","author":"Beck","year":"1959","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"B3","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1111\/mmi.14565","article-title":"Combatting the evolution of antifungal resistance in Cryptococcus neoformans","volume":"114","author":"Bermas","year":"2020","journal-title":"Mol. Microbiol."},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3390\/jof3040057","article-title":"Global and multi-national prevalence of fungal diseases-estimate precision","volume":"3","author":"Bongomin","year":"2017","journal-title":"J. Fungi (Basel)"},{"key":"B5","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1111\/myc.12747","article-title":"A systematic review of fluconazole resistance in clinical isolates of Cryptococcus species","volume":"61","author":"Bongomin","year":"2018","journal-title":"Mycoses"},{"key":"B6","doi-asserted-by":"publisher","first-page":"e01952","DOI":"10.1128\/mBio.01952-19","article-title":"A mechanosensitive channel governs lipid flippase-mediated echinocandin resistance in","volume":"10","author":"Cao","year":"2019","journal-title":"Cryptococcus Neoformans mBio"},{"key":"B7","unstructured":"Fungal diseases2020"},{"key":"B8","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1016\/j.cell.2015.01.026","article-title":"Targeting the adaptability of heterogeneous aneuploids","volume":"160","author":"Chen","year":"2015","journal-title":"Cell"},{"volume-title":"Reference method for broth dilution antifungal susceptibility testing of yeasts; approved standard-4th ed. CLSI document M27-A4","year":"2017","key":"B9"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1937","DOI":"10.1093\/jac\/dks137","article-title":"In vitro antifungal susceptibility of filamentous fungi causing rare infections: synergy testing of amphotericin b, posaconazole and anidulafungin in pairs","volume":"67","author":"Drogari-Apiranthitou","year":"2012","journal-title":"J. Antimicrob. Chemother."},{"key":"B11","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1111\/j.1349-7006.2004.tb03330.x","article-title":"Antitumor activity of pyrvinium pamoate, 6-(dimethylamino)-2-[2-(2,5-dimethyl-1-phenyl-1H-pyrrol-3-yl)ethenyl]-1-methyl-quinolinium pamoate salt, showing preferential cytotoxicity during glucose starvation","volume":"95","author":"Esumi","year":"2004","journal-title":"Cancer Sci."},{"key":"B12","first-page":"1195","article-title":"Major helminthic diseases of north America: A review","volume":"6","author":"Fozard","year":"1978","journal-title":"J. Fam. Pract."},{"key":"B13","doi-asserted-by":"publisher","first-page":"e02361","DOI":"10.1128\/AAC.02361-17","article-title":"Synergy between pyrvinium pamoate and azoles against Exophiala dermatitidis","volume":"62","author":"Gao","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"B14","doi-asserted-by":"publisher","first-page":"e02108","DOI":"10.1128\/AAC.02108-16","article-title":"Physiological differences in Cryptococcus neoformans strains in vitro versus in vivo and their effects on antifungal susceptibility","volume":"61","author":"Grossman","year":"2017","journal-title":"Antimicrob. Agents Chemother."},{"key":"B15","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.canlet.2011.12.034","article-title":"Pyrvinium pamoate inhibits proliferation of myeloma\/erythroleukemia cells by suppressing mitochondrial respiratory complex I and STAT3","volume":"319","author":"Harada","year":"2012","journal-title":"Cancer Lett."},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2012.00137","article-title":"Reprofiling a classical anthelmintic, pyrvinium pamoate, as an anti-cancer drug targeting mitochondrial respiration","volume":"2","author":"Ishii","year":"2012","journal-title":"Front. Oncol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.fbr.2014.07.001","article-title":"Endoplasmic reticulum stress and fungal pathogenesis","volume":"28","author":"Krishnan","year":"2014","journal-title":"Fungal Bio. Rev."},{"key":"B18","doi-asserted-by":"publisher","first-page":"e1003022","DOI":"10.1371\/journal.ppat.1003022","article-title":"Aneuploidy and drug resistance in pathogenic fungi","volume":"8","author":"Kwon-Chung","year":"2012","journal-title":"PloS Pathog."},{"key":"B19","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1097\/QCO.0b013e32835c21d1","article-title":"Cryptococcal immune reconstitution inflammatory syndrome","volume":"26","author":"Longley","year":"2013","journal-title":"Curr. Opin. Infect. Dis."},{"key":"B20","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1016\/S1473-3099(13)70078-1","article-title":"Cryptococcal meningitis: improving access to essential antifungal medicines in resource-poor countries","volume":"13","author":"Loyse","year":"2013","journal-title":"Infect. Dis."},{"key":"B21","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1080\/21505594.2015","article-title":"Galleria mellonella as a host model to study Aspergillus terreus virulence and amphotericin b resistance","volume":"6","author":"Maurer","year":"2015","journal-title":"Virulence"},{"key":"B22","doi-asserted-by":"publisher","first-page":"189","DOI":"10.3201\/eid0902.020246","article-title":"Molecular typing of ibero American cryptococcus neoformans isolates","volume":"9","author":"Meyer","year":"2003","journal-title":"Emerg. Infect. Dis."},{"key":"B23","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1086\/368091","article-title":"The changing epidemiology of cryptococcosis: an update from population-based active surveillance in 2 large metropolitan areas 1992-2000","volume":"36","author":"Mirza","year":"2003","journal-title":"Clini. Infect. Dis."},{"key":"B24","doi-asserted-by":"publisher","first-page":"2871","DOI":"10.1002\/jcp.26006","article-title":"The novel role of pyrvinium in cancer therapy","volume":"233","author":"Momtazi-Borojeni","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkg301","article-title":"Synergy, antagonism, and what the chequerboard puts between them","volume":"52","author":"Odds","year":"2003","journal-title":"J. Antimicrob. Chemother."},{"key":"B26","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1038\/nrd.2017.46","article-title":"The antifungal pipeline: a reality check","volume":"16","author":"Perfect","year":"2017","journal-title":"Nat Rev Drug Discov."},{"key":"B27","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1086\/649858","article-title":"Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america","volume":"50","author":"Perfect","year":"2010","journal-title":"Clini. Infect. Dis."},{"key":"B28","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1128\/JCM.01747-08","article-title":"Results from the ARTEMIS DISK global antifungal surveillance study 1997 to 2007: 10.5-year analysis of susceptibilities of noncandidal yeast species to fluconazole and voriconazole determined by CLSI standardized disk diffusion testing","volume":"47","author":"Pfaller","year":"2009","journal-title":"J. Clini. Microbiol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1016\/S1473-3099(17)30243-8","article-title":"Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis","volume":"17","author":"Rajasingham","year":"2017","journal-title":"Infect. Dis."},{"key":"B30","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1126\/science.1128242","article-title":"Aneuploidy and isochromosome formation in drug-resistant Candida albicans","volume":"313","author":"Selmecki","year":"2006","journal-title":"Science"},{"key":"B31","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1042\/BST0340356","article-title":"Sterol trafficking between the endoplasmic reticulum and plasma membrane in yeast","volume":"34","author":"Sullivan","year":"2006","journal-title":"Biochem. Soc Trans."},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2020.576975","article-title":"In vitro and in vivo study of antifungal effect of pyrvinium pamoate alone and in combination with azoles against Exophiala dermatitidis","volume":"10","author":"Sun","year":"2020","journal-title":"Front. Cell. Infect. Mi."},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2020.579362","article-title":"Synergistic effect of pyrvinium pamoate and azoles against Aspergillus fumigatus in vitro and in vivo","volume":"11","author":"Sun","year":"2020","journal-title":"Front. Microbiol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1534\/genetics.108.090878","article-title":"Aneuploidy: cells losing their balance","volume":"179","author":"Torres","year":"2008","journal-title":"Genetics"},{"key":"B35","doi-asserted-by":"publisher","first-page":"3394","DOI":"10.1128\/AAC.46.11.3394-3400.2002","article-title":"Melanization of Cryptococcus neoformans and histoplasma capsulatum reduces their susceptibilities to amphotericin b and caspofungin","volume":"46","author":"van Duin","year":"2002","journal-title":"Antimicrob. Agents Chemother."},{"key":"B36","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1038\/nrneurol.2016.167","article-title":"Cryptococcal meningitis: epidemiology, immunology, diagnosis and therapy","volume":"13","author":"Williamson","year":"2016","journal-title":"Nat. Rev. Neurol."},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1128\/Spectrum.00723-21","article-title":"Adaptation to fluconazole via aneuploidy enables cross-adaptation to amphotericin b and flucytosine in Cryptococcus neoformans","volume":"9","author":"Yang","year":"2021","journal-title":"Microbiol. Spectr."},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0003951","article-title":"Pyrvinium targets the unfolded protein response to hypoglycemia and its anti-tumor activity is enhanced by combination therapy","volume":"3","author":"Yu","year":"2008","journal-title":"PloS One"}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.1074903\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,9]],"date-time":"2022-12-09T06:09:18Z","timestamp":1670566158000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.1074903\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,9]]},"references-count":38,"alternative-id":["10.3389\/fcimb.2022.1074903"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2022.1074903","relation":{},"ISSN":["2235-2988"],"issn-type":[{"type":"electronic","value":"2235-2988"}],"subject":[],"published":{"date-parts":[[2022,12,9]]},"article-number":"1074903"}}