{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T19:24:05Z","timestamp":1790364245168,"version":"4.1.0"},"reference-count":50,"publisher":"American Society for Microbiology","issue":"4","license":[{"start":{"date-parts":[[2018,4,1]],"date-time":"2018-04-01T00:00:00Z","timestamp":1522540800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"DIR, NIAID, NIH"},{"name":"DIR, NIAID, NIH"},{"name":"DIR, NIAID, NIH"},{"name":"DIR, NIAID, NIH"},{"name":"DIR, NIAID, NIH"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2018,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            <jats:named-content content-type=\"genus-species\">Cryptococcus neoformans<\/jats:named-content>\n            and\n            <jats:named-content content-type=\"genus-species\">Cryptococcus gattii<\/jats:named-content>\n            species complexes are the etiologic agents of cryptococcosis. We have deciphered the roles of three ABC transporters, Afr1, Afr2, and Mdr1, in the representative strains of the two species,\n            <jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>\n            H99 and\n            <jats:named-content content-type=\"genus-species\">C. gattii<\/jats:named-content>\n            R265. Deletion of\n            <jats:italic>AFR1<\/jats:italic>\n            in H99 and R265 drastically reduced the levels of resistance to three xenobiotics and three triazoles, suggesting that Afr1 is the major drug efflux pump in both strains. Fluconazole susceptibility was not affected when\n            <jats:italic>AFR2<\/jats:italic>\n            or\n            <jats:italic>MDR1<\/jats:italic>\n            was deleted in both strains. However, when these genes were deleted in combination with\n            <jats:italic>AFR1<\/jats:italic>\n            , a minor additive effect in susceptibility toward several drugs was observed. Deletion of all three genes in both strains caused further increases in susceptibility toward fluconazole and itraconazole, suggesting that Afr2 and Mdr1 augment Afr1 function in pumping these triazoles. Intracellular accumulation of Nile Red significantly increased in\n            <jats:italic>afr1\u0394<\/jats:italic>\n            mutants of both strains, but rhodamine 6G accumulation increased only in the\n            <jats:italic>mdr1\u0394<\/jats:italic>\n            mutant of H99. Thus, the three efflux pumps play different roles in the two strains when exposed to different azoles and xenobiotics.\n            <jats:italic>AFR1<\/jats:italic>\n            and\n            <jats:italic>AFR2<\/jats:italic>\n            expression was upregulated in H99 and R265 when treated with fluconazole. However,\n            <jats:italic>MDR1<\/jats:italic>\n            expression was upregulated only in R265 under the same conditions. We screened a library of transcription factor mutants and identified several mutants that manifested either altered fluconazole sensitivity or an increase in the frequency of fluconazole heteroresistance. Gene expression analysis suggests that the three efflux pumps are regulated independently by different transcription factors in response to fluconazole exposure.\n          <\/jats:p>","DOI":"10.1128\/aac.01751-17","type":"journal-article","created":{"date-parts":[[2018,1,27]],"date-time":"2018-01-27T11:28:02Z","timestamp":1517052482000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":61,"title":["Roles of Three Cryptococcus neoformans and Cryptococcus gattii Efflux Pump-Coding Genes in Response to Drug Treatment"],"prefix":"10.1128","volume":"62","author":[{"given":"Miwha","family":"Chang","sequence":"first","affiliation":[{"name":"Molecular Microbiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Sionov","sequence":"additional","affiliation":[{"name":"Department of Food Quality and Safety, Institute for Postharvest and Food Sciences, The Volcani Center, Agricultural Research Organization, Rishon LeZion, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ami","family":"Khanal Lamichhane","sequence":"additional","affiliation":[{"name":"Molecular Microbiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyung J.","family":"Kwon-Chung","sequence":"additional","affiliation":[{"name":"Molecular Microbiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun C.","family":"Chang","sequence":"additional","affiliation":[{"name":"Molecular Microbiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/mSphere.00357-16"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.3390\/jof1020154"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1086\/649858"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2736(72)90046-6"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(88)90232-X"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1080\/13693780500138971"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0213-005X(02)72842-5"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-2008-1063858"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/clinids\/19.5.975-a"},{"key":"e_1_3_3_11_2","first-page":"249","article-title":"Amphotericin-B induced changes in renal membrane ion permeation\u2014model of nephrotoxicity","volume":"65","author":"Schell RE","year":"1986","unstructured":"Schell RE, Tran NV, Bramhall JS. 1986. 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