{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T20:40:12Z","timestamp":1788813612107,"version":"build-2803163510"},"reference-count":35,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2015,8,1]],"date-time":"2015-08-01T00:00:00Z","timestamp":1438387200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2015,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Cryptococcus gattii<\/jats:named-content>\n            is the main etiological agent of cryptococcosis in immunocompetent individuals. The triazole drug itraconazole is one of the antifungals used to treat patients with cryptococcosis. Heteroresistance is an adaptive mechanism to counteract the stress of increasing drug concentrations, and it can enhance the ability of a microorganism to survive under antifungal pressure. In this study, we evaluated the ability of 11\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">C. gattii<\/jats:named-content>\n            strains to develop itraconazole heteroresistance. Heteroresistant clones were analyzed for drug susceptibility, alterations in cell diameter, capsule properties, and virulence in a murine model. Heteroresistance to itraconazole was intrinsic in all of the strains analyzed, reduced both the capsule size and the cell diameter, induced molecular heterogeneity at the chromosomal level, changed the negatively charged cells, reduced ergosterol content, and improved the antioxidant system. A positive correlation between surface\/volume ratio of original cells and the level of heteroresistance to itraconazole (LHI) was observed in addition to a negative correlation between capsule size of heteroresistant clones and LHI. Moreover, heteroresistance to itraconazole increased the engulfment of\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">C. gattii<\/jats:named-content>\n            by macrophages and augmented fungal proliferation inside these cells, which probably accounted for the reduced survival of the mice infected with the heteroresistant clones and the higher fungal burden in lungs and brain. Our results indicate that heteroresistance to itraconazole is intrinsic and increases the virulence of\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">C. gattii<\/jats:named-content>\n            . This phenomenon may represent an additional mechanism that contributes to relapses of cryptococcosis in patients during itraconazole therapy.\n          <\/jats:p>","DOI":"10.1128\/aac.00466-15","type":"journal-article","created":{"date-parts":[[2015,5,27]],"date-time":"2015-05-27T15:24:53Z","timestamp":1432740293000},"page":"4600-4609","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":40,"title":["Heteroresistance to Itraconazole Alters the Morphology and Increases the Virulence of Cryptococcus gattii"],"prefix":"10.1128","volume":"59","author":[{"given":"Gabriella Freitas","family":"Ferreira","sequence":"first","affiliation":[{"name":"Departamento de Microbiologia, Instituto de Ci\u00eancias Biol\u00f3gicas, Universidade Federal de Minas Gerais, Pampulha, Belo Horizonte, Minas Gerais, Brazil"},{"name":"Departamento de Farm\u00e1cia, Universidade Federal de Juiz de Fora\u2013Campus Governador Valadares, Centro, Governador Valadares, Minas Gerais, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julliana Ribeiro Alves","family":"Santos","sequence":"additional","affiliation":[{"name":"Departamento de Microbiologia, Instituto de Ci\u00eancias Biol\u00f3gicas, Universidade Federal de Minas Gerais, Pampulha, Belo Horizonte, Minas Gerais, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marliete Carvalho da","family":"Costa","sequence":"additional","affiliation":[{"name":"Departamento de Microbiologia, Instituto de Ci\u00eancias Biol\u00f3gicas, Universidade Federal de Minas Gerais, Pampulha, Belo Horizonte, Minas Gerais, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodrigo Assun\u00e7\u00e3o de","family":"Holanda","sequence":"additional","affiliation":[{"name":"Departamento de Microbiologia, Instituto de Ci\u00eancias Biol\u00f3gicas, Universidade Federal de Minas Gerais, Pampulha, Belo Horizonte, Minas Gerais, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c2ngelo M\u00e1rcio Leite","family":"Denadai","sequence":"additional","affiliation":[{"name":"Departamento de Farm\u00e1cia, Universidade Federal de Juiz de Fora\u2013Campus Governador Valadares, Centro, Governador Valadares, Minas Gerais, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo Jos\u00e9 Cota de","family":"Freitas","sequence":"additional","affiliation":[{"name":"Departamento de Microbiologia, Instituto de Ci\u00eancias Biol\u00f3gicas, Universidade Federal de Minas Gerais, Pampulha, Belo Horizonte, Minas Gerais, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1quila Rodrigues Costa","family":"Santos","sequence":"additional","affiliation":[{"name":"Universidade Vale do Rio Doce, Universit\u00e1rio, Governador Valadares, Minas Gerais, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priscila Batista","family":"Tavares","sequence":"additional","affiliation":[{"name":"Universidade Vale do Rio Doce, Universit\u00e1rio, Governador Valadares, Minas Gerais, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiane Alves","family":"Paix\u00e3o","sequence":"additional","affiliation":[{"name":"Departamento de Microbiologia, Instituto de Ci\u00eancias Biol\u00f3gicas, Universidade Federal de Minas Gerais, Pampulha, Belo Horizonte, Minas Gerais, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel Assis","family":"Santos","sequence":"additional","affiliation":[{"name":"Departamento de Microbiologia, Instituto de Ci\u00eancias Biol\u00f3gicas, Universidade Federal de Minas Gerais, Pampulha, Belo Horizonte, Minas Gerais, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.2217\/fmb.13.123"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-2008-1063858"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00295-09"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00153-10"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-0691.2007.01912.x"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000848"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1086\/649858"},{"key":"e_1_3_2_9_2","doi-asserted-by":"crossref","first-page":"2301","DOI":"10.1001\/archinte.1989.00390100107024","article-title":"Itraconazole therapy for cryptococcal meningitis and cryptococcosis","volume":"10","author":"Denning DW","year":"1989","unstructured":"Denning DW, Tucker RM, Hanson LH, Hamilton JR, Stevens DA. 1989. 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