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Although the organoselenium compound LQA_78 previously demonstrated antifungal activity against Cryptococcus neoformans, its effect on C. gattii remains unclear. Then, the aim of this work is to evaluate the antifungal activity of LQA_78 against C. gattii strains, its effects on virulence factors, and the underlying mechanisms of fungal cell death. Clinical isolates and morphotypes of C. gattii were subjected to susceptibility testing to determine inhibitory and fungicidal concentrations. Capsule thickness and permeability, melanin production, and laccase activity were assessed. Oxidative stress parameters, including reactive oxygen species (ROS) production, lipid peroxidation, glutathione (GSH) levels, and superoxide dismutase activity, were evaluated. Mitochondrial membrane potential, DNA fragmentation, and chromatin condensation were analyzed to investigate cell death pathways. In vivo efficacy was assessed using the Galleria mellonella infection model. LQA_78 inhibited fungal growth at concentrations comparable to fluconazole (2\u201332 \u03bcg\/mL), increased capsule permeability without reduction in capsule thickness, and melanin production and laccase activity were significantly reduced. LQA_78, at higher concentrations (16\u201332 \u03bcg\/mL), induced and increased plasma membrane permeability, lipid peroxidation, ROS accumulation, GSH depletion, reduced superoxide dismutase activity, mitochondrial dysfunction, DNA fragmentation, chromatin condensation, and phosphatidylserine externalization, indicating apoptosis- and necrosis-like cell death. In G. mellonella, nontoxic doses reduced the larvae mortality and fungal burden and increased hemocyte density. Therefore, the organoselenium LQA_78 demonstrates significant in vitro and in vivo antifungal activity against C. gattii, supporting its potential as a lead compound for cryptococcosis therapy.<\/jats:p>","DOI":"10.1021\/acsomega.6c02274","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T18:26:13Z","timestamp":1784053573000},"page":"43540-43554","source":"Crossref","is-referenced-by-count":1,"title":["An Organoselenium\nCompound Induces Death in\n                    <i>Cryptococcus gattii<\/i>\n                    Yeast by Apoptosis and Necrosis\nand Shows Antifungal Efficacy in\n                    <i>Galleria mellonella<\/i>"],"prefix":"10.1021","volume":"11","author":[{"given":"Leti\u0301cia Serafim","family":"da Costa","sequence":"first","affiliation":[{"name":"University of Sa\u0303o Paulo (USP) , , 1374 Prof. Lineu Prestes Avenue , , ,","place":["Sa\u0303o Paulo, SP, Brazil, 05508-000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel Felipe Freitas de","family":"Jesus","sequence":"additional","affiliation":[{"name":"University of Sa\u0303o Paulo (USP) , , 1374 Prof. Lineu Prestes Avenue , , ,","place":["Sa\u0303o Paulo, SP, Brazil, 05508-000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larissa","family":"Dunkl Brujas","sequence":"additional","affiliation":[{"name":"University of Sa\u0303o Paulo (USP) , , 1374 Prof. Lineu Prestes Avenue , , ,","place":["Sa\u0303o Paulo, SP, Brazil, 05508-000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isadora Maria","family":"de Oliveira","sequence":"additional","affiliation":[{"name":"University of Sa\u0303o Paulo (USP) , , 580 Prof. Lineu Prestes Avenue , , ,","place":["Sa\u0303o Paulo, SP, Brazil, 05508-000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael Wesley","family":"Bastos","sequence":"additional","affiliation":[{"name":"Federal University of Rio Grande do Norte (UFRN) , , 3000 Sen Salgado Filho Avenue , , ,","place":["Natal, RN, Brazil, 59064-741"]},{"name":"Brazilian National Institute of Science and Technology in Human Pathogenic Fungi (INCT-FUNVIR , , ,","place":["Ribeira\u0303o Preto, SP, Brazil, 14049-900"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Analy Salles de Azevedo","family":"Melo","sequence":"additional","affiliation":[{"name":"Federal University of Sa\u0303o Paulo (UNIFESP) , , 740 Botucatu Street , , ,","place":["Sa\u0303o Paulo, SP, Brazil, 04023-062"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1108-5666","authenticated-orcid":true,"given":"Daniel Assis","family":"Santos","sequence":"additional","affiliation":[{"name":"Federal University of Minas Gerais (UFMG) , , 6627 Pres. Anto\u0302nio Carlos Avenue , , ,","place":["Belo Horizonte, MG, Brazil, 31270-901"]},{"name":"Brazilian National Institute of Science and Technology in Human Pathogenic Fungi (INCT-FUNVIR , , ,","place":["Ribeira\u0303o Preto, SP, Brazil, 14049-900"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7805-2834","authenticated-orcid":true,"given":"He\u0301lio A.","family":"Stefani","sequence":"additional","affiliation":[{"name":"University of Sa\u0303o Paulo (USP) , , 580 Prof. Lineu Prestes Avenue , , ,","place":["Sa\u0303o Paulo, SP, Brazil, 05508-000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4602-0926","authenticated-orcid":true,"given":"Kelly","family":"Ishida","sequence":"additional","affiliation":[{"name":"University of Sa\u0303o Paulo (USP) , , 1374 Prof. Lineu Prestes Avenue , , ,","place":["Sa\u0303o Paulo, SP, Brazil, 05508-000"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"issue":"3","key":"2026072810110829300_cit1","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00103-12","article-title":"The primary\ntarget organ of Cryptococcus gattii is different\nfrom that of Cryptococcus neoformans in a murine\nmodel","volume":"3","author":"Ngamskulrungroj","year":"2012","journal-title":"mBio"},{"issue":"3","key":"2026072810110829300_cit2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0011162","article-title":"Epidemiology, management\nand outcomes of Cryptococcus gattii infections: A\n22-year cohort","volume":"17","author":"O\u2019Hern","year":"2023","journal-title":"PLoS Negl. 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Immunol."},{"issue":"5","key":"2026072810110829300_cit7","doi-asserted-by":"publisher","DOI":"10.1128\/mSphere.00644-19","article-title":"Chitosan biosynthesis and virulence\nin the human fungal pathogen Cryptococcus gattii","volume":"4","author":"Lam","year":"2019","journal-title":"mSphere"},{"issue":"5","key":"2026072810110829300_cit8","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.02016-18","article-title":"Phenotypic\nvariability correlates\nwith clinical outcome in Cryptococcus isolates obtained\nfrom Botswanan HIV\/AIDS patients","volume":"9","author":"Fernandes","year":"2018","journal-title":"mBio"},{"issue":"11","key":"2026072810110829300_cit9","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\ntheir susceptibilities to amphotericin B and caspofungin","volume":"46","author":"van Duin","year":"2002","journal-title":"Antimicrob. 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Mycol."},{"issue":"24","key":"2026072810110829300_cit18","doi-asserted-by":"publisher","first-page":"2663","DOI":"10.1080\/17568919.2024.2435254","article-title":"Organoselenium\ncompounds\nbeyond antioxidants","volume":"16","author":"Mamgain","year":"2024","journal-title":"Future Med. Chem."},{"issue":"5","key":"2026072810110829300_cit19","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1093\/mmy\/myaa115","article-title":"Ebselen\nand diphenyl diselenide against\nfungal pathogens: A systematic review","volume":"59","author":"Benelli","year":"2021","journal-title":"Med.\nMycol."},{"issue":"7","key":"2026072810110829300_cit20","doi-asserted-by":"publisher","first-page":"3213","DOI":"10.1039\/d4md00677a","article-title":"Organoselenium compounds as an enriched\nsource for the discovery of new antimicrobial agents","volume":"16","author":"Friberg","year":"2025","journal-title":"RSC Med. 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Agents\nChemother."},{"key":"2026072810110829300_cit24","doi-asserted-by":"publisher","first-page":"101359","DOI":"10.1016\/j.drup.2026.101359","article-title":"Acetylation-mediated\nfluconazole inactivation: A novel antifungal resistance mechanism","volume":"85","author":"Gouveia-Eufrasio","year":"2026","journal-title":"Drug Resist. Updat."},{"issue":"1","key":"2026072810110829300_cit25","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1080\/22221751.2018.1562849","article-title":"Genotypic diversity\nand clinical outcome of cryptococcosis in renal transplant recipients\nin Brazil","volume":"8","author":"Ponzio","year":"2019","journal-title":"Emerg. Microbes Infect."},{"key":"2026072810110829300_cit26","doi-asserted-by":"publisher","first-page":"9884","DOI":"10.1039\/C7NJ01803G","article-title":"Ytterbium(III)-catalyzed\nthree-component reactions: Synthesis of 4-organoselenium-quinolines","volume":"41","author":"de Oliveira","year":"2017","journal-title":"New J. Chem."},{"key":"2026072810110829300_cit27","volume-title":"Reference Method for Broth\nDilution Antifungal Susceptibility Testing of Yeasts","author":"Clinical and Laboratory Standards Institute.","year":"2017","edition":"4"},{"key":"2026072810110829300_cit28","doi-asserted-by":"publisher","first-page":"542","DOI":"10.3390\/jof9050542","article-title":"Methods for antifungal susceptibility testing of the Cryptococcus neoformans\/C. gattii complex: Strengths and\nlimitations","volume":"9","author":"Espinel-Ingroff","year":"2023","journal-title":"J. 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Antimicrob."},{"issue":"4","key":"2026072810110829300_cit36","doi-asserted-by":"publisher","first-page":"393","DOI":"10.3390\/jof8040393","article-title":"Faster Cryptococcus melanization increases virulence in experimental and human cryptococcosis","volume":"8","author":"de Sousa","year":"2022","journal-title":"J. Fungi"},{"issue":"5","key":"2026072810110829300_cit37","doi-asserted-by":"publisher","first-page":"1207","DOI":"10.1128\/AAC.42.5.1207","article-title":"Influence\nof test conditions on antifungal time-kill curve results: Proposal\nfor standardized methods","volume":"42","author":"Klepser","year":"1998","journal-title":"Antimicrob. Agents\nChemother."},{"issue":"5","key":"2026072810110829300_cit38","doi-asserted-by":"publisher","first-page":"2504","DOI":"10.1128\/AAC.01654-13","article-title":"Synthesis\nand antifungal activity in vitro of isoniazid derivatives against Histoplasma capsulatum var. capsulatum","volume":"58","author":"de Aguiar Cordeiro","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"issue":"8","key":"2026072810110829300_cit39","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00312-18","article-title":"Miltefosine has a postantifungal\neffect and induces apoptosis in Cryptococcus yeasts","volume":"62","author":"Spadari","year":"2018","journal-title":"Antimicrob. 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Immun."},{"issue":"3","key":"2026072810110829300_cit45","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1080\/mmy.38.3.201.207","article-title":"Time-kill\ncurves for Cryptococcus neoformans isolated from\npatients with AIDS","volume":"38","author":"Rodero","year":"2000","journal-title":"Med. Mycol."},{"key":"2026072810110829300_cit46","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.fgb.2014.11.006","article-title":"Immunity to Cryptococcus\nneoformans and C. gattii during\ncryptococcosis","volume":"78","author":"Gibson","year":"2015","journal-title":"Fungal Genet. Biol."},{"issue":"3","key":"2026072810110829300_cit47","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00712-19","article-title":"Contribution\nof laccase expression\nto immune response against Cryptococcus gattii infection","volume":"88","author":"Hansakon","year":"2020","journal-title":"Infect. Immun."},{"issue":"2","key":"2026072810110829300_cit48","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1005397","article-title":"Go forth and colonize: Dispersal from clinically important\nmicrobial biofilms","volume":"12","author":"Uppuluri","year":"2016","journal-title":"PLoS Pathog."},{"issue":"10","key":"2026072810110829300_cit49","doi-asserted-by":"publisher","first-page":"2043","DOI":"10.1111\/j.1462-5822.2008.01186.x","article-title":"Capsule enlargement\nin Cryptococcus neoformans confers resistance to\noxidative stress suggesting a mechanism for intracellular survival","volume":"10","author":"Zaragoza","year":"2008","journal-title":"Cell. Microbiol."},{"issue":"3","key":"2026072810110829300_cit50","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0011162","article-title":"Epidemiology,\nmanagement\nand outcomes of Cryptococcus gattii infections: A\n22-year cohort","volume":"17","author":"O\u2019Hern","year":"2023","journal-title":"PLoS Negl. Trop. Dis."},{"issue":"7","key":"2026072810110829300_cit51","doi-asserted-by":"publisher","first-page":"1133","DOI":"10.1093\/cid\/ciab268","article-title":"MSG07: An international\ncohort study\ncomparing epidemiology and outcomes of patients with Cryptococcus neoformans or Cryptococcus gattii infections","volume":"73","author":"Baddley","year":"2021","journal-title":"Clin. Infect. 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