{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T22:17:42Z","timestamp":1793744262818,"version":"4.6.1"},"reference-count":32,"publisher":"American Society for Microbiology","issue":"6","license":[{"start":{"date-parts":[[2000,3,15]],"date-time":"2000-03-15T00:00:00Z","timestamp":953078400000},"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":["J Bacteriol"],"published-print":{"date-parts":[[2000,3,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Adaptation to inhibitory concentrations of the antifungal agent fluconazole was monitored in replicated experimental populations founded from a single, drug-sensitive cell of the yeast\n            <jats:italic>Candida albicans<\/jats:italic>\n            and reared over 330 generations. The concentration of fluconazole was maintained at twice the MIC in six populations; no fluconazole was added to another six populations. All six replicate populations grown with fluconazole adapted to the presence of drug as indicated by an increase in MIC; none of the six populations grown without fluconazole showed any change in MIC. In all populations evolved with drug, increased fluconazole resistance was accompanied by increased resistance to ketoconazole and itraconazole; these populations contained ergosterol in their cell membranes and were amphotericin sensitive. The increase in fluconazole MIC in the six populations evolved with drug followed different trajectories, and these populations achieved different levels of resistance, with distinct overexpression patterns of four genes involved in azole resistance: the ATP-binding cassette transporter genes,\n            <jats:italic>CDR1<\/jats:italic>\n            and\n            <jats:italic>CDR2<\/jats:italic>\n            ; the gene encoding the target enzyme of the azoles in the ergosterol biosynthetic pathway,\n            <jats:italic>ERG11<\/jats:italic>\n            ; and the major facilitator gene,\n            <jats:italic>MDR1<\/jats:italic>\n            . Selective sweeps in these populations were accompanied by additional genomic changes with no known relationship to drug resistance: loss of heterozygosity in two of the five marker genes assayed and alterations in DNA fingerprints and electrophoretic karyotypes. These results show that chance, in the form of mutations that confer an adaptive advantage, is a determinant in the evolution of azole drug resistance in experimental populations of\n            <jats:italic>C. albicans.<\/jats:italic>\n          <\/jats:p>","DOI":"10.1128\/jb.182.6.1515-1522.2000","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T10:03:59Z","timestamp":1027764239000},"page":"1515-1522","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":184,"title":["Evolution of Drug Resistance in Experimental Populations of\n            <i>Candida albicans<\/i>"],"prefix":"10.1128","volume":"182","author":[{"given":"Leah E.","family":"Cowen","sequence":"first","affiliation":[{"name":"<!--label omitted: 1-->Department of Botany, University of Toronto, Mississauga, Ontario, Canada L5L 1C6,1 and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"Sanglard","sequence":"additional","affiliation":[{"name":"<!--label omitted: 2-->Institute of Microbiology, University Hospital, 1011 Lausanne, Switzerland2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Calabrese","sequence":"additional","affiliation":[{"name":"<!--label omitted: 2-->Institute of Microbiology, University Hospital, 1011 Lausanne, Switzerland2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Sirjusingh","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Department of Botany, University of Toronto, Mississauga, Ontario, Canada L5L 1C6,1 and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James B.","family":"Anderson","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Department of Botany, University of Toronto, Mississauga, Ontario, Canada L5L 1C6,1 and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda M.","family":"Kohn","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Department of Botany, University of Toronto, Mississauga, Ontario, Canada L5L 1C6,1 and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1126\/science.283.5400.404","article-title":"Diminishing returns from mutation supply rate in asexual populations","volume":"283","author":"Arjan J. A.","year":"1999","unstructured":"Arjan J. A. Visser M. Zeyl C. W. Gerrish P. J. Blanchard J. L. Lenski R. E. Diminishing returns from mutation supply rate in asexual populations.Science2831999404406","journal-title":"Science"},{"key":"e_1_3_2_3_2","unstructured":"Ausubel\nF. M.\nPreparation of yeast RNA\nCurrent protocols in molecular biology.\nAusubel\nF. M.\nBrent\nR.\nKingston\nR. E.\nMoore\nD. D.\nSeidman\nJ. G.\nSmith\nJ. A.\nStruhl\nK.\n1995\n13.12.2\n13.12.3\nJohn Wiley & Sons Inc.\nNew York N.Y"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/jb.175.20.6637-6651.1993"},{"key":"e_1_3_2_5_2","doi-asserted-by":"crossref","first-page":"2930","DOI":"10.1128\/AAC.43.12.2930","article-title":"Multilocus genotypes and DNA fingerprints do not predict variation in azole resistance among clinical isolates of Candida albicans","volume":"12","author":"Cowen L. E.","year":"1999","unstructured":"Cowen L. E. Sirjusingh C. Summerbell R. C. Walmsley S. Richardson S. Kohn L. M. Anderson J. B. Multilocus genotypes and DNA fingerprints do not predict variation in azole resistance among clinical isolates of Candida albicans.Antimicrob. Agents Chemother.12199929302938","journal-title":"Antimicrob. Agents Chemother."},{"key":"e_1_3_2_6_2","doi-asserted-by":"crossref","first-page":"9721","DOI":"10.1073\/pnas.96.17.9721","article-title":"Systematic changes in gene expression patterns following adaptive evolution in yeast","volume":"96","author":"Ferea T. L.","year":"1999","unstructured":"Ferea T. L. Botstein D. Brown P. O. Rosenzweig R. F. Systematic changes in gene expression patterns following adaptive evolution in yeast.Proc. Natl. Acad. Sci. USA96199997219726","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"e_1_3_2_7_2","doi-asserted-by":"crossref","first-page":"12473","DOI":"10.1073\/pnas.93.22.12473","article-title":"Molecular markers reveal that population structure of the human pathogen Candida albicans exhibits both clonality and recombination","volume":"93","author":"Gr\u00e4ser Y.","year":"1996","unstructured":"Gr\u00e4ser Y. Volovsek M. Arrington J. Sch\u00f6nian G. Presber W. Mitchell T. G. Vilgalys R. Molecular markers reveal that population structure of the human pathogen Candida albicans exhibits both clonality and recombination.Proc. Natl. Acad. Sci. USA9319961247312477","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.285.5431.1271"},{"key":"e_1_3_2_9_2","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1099\/00221287-138-6-1177","article-title":"Clonal variation of chromosome size derived from the rDNA cluster region in Candida albicans","volume":"138","author":"Iwaguchi S.","year":"1992","unstructured":"Iwaguchi S. Homma M. Tanaka K. Clonal variation of chromosome size derived from the rDNA cluster region in Candida albicans.J. Gen. Microbiol.138199211771184","journal-title":"J. Gen. Microbiol."},{"key":"e_1_3_2_10_2","doi-asserted-by":"crossref","first-page":"6808","DOI":"10.1073\/pnas.91.15.6808","article-title":"Dynamics of adaptation and diversification: a 10,000-generation experiment with bacterial populations","volume":"91","author":"Lenski R. E.","year":"1994","unstructured":"Lenski R. E. Travisano M. Dynamics of adaptation and diversification: a 10,000-generation experiment with bacterial populations.Proc. Natl. Acad. Sci. USA91199468086814","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.43.6.1383"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.3.4.321"},{"key":"e_1_3_2_13_2","unstructured":"National Committee for Clinical Laboratory Standards\nReference method for broth dilution antifungal susceptibility testing of yeasts. Approved standard. NCCLS document M27-A.\n1997\nNational Committee for Clinical Laboratory Standards\nWayne Pa"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.181.13.4041-4049.1999"},{"key":"e_1_3_2_15_2","doi-asserted-by":"crossref","first-page":"9456","DOI":"10.1073\/pnas.90.20.9456","article-title":"The yeast Candida albicans has a clonal mode of reproduction in a population of infected human immunodeficiency virus-positive patients","volume":"90","author":"Pujol C.","year":"1993","unstructured":"Pujol C. Reynes J. Renaud F. Raymond M. Tibayrenc M. Ayala F. J. Janbon F. Mallie M. Bastide J. M. The yeast Candida albicans has a clonal mode of reproduction in a population of infected human immunodeficiency virus-positive patients.Proc. Natl. Acad. Sci. USA90199394569459","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/jb.175.22.7189-7199.1993"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/jb.172.3.1276-1283.1990"},{"key":"e_1_3_2_18_2","unstructured":"Sambrook\nJ.\nFritsch\nE. F.\nManiatis\nT.\nMolecular cloning: a laboratory manual\n2nd ed.\n1989\nCold Spring Harbor Laboratory Press\nCold Spring Harbor N.Y"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.42.2.241"},{"key":"e_1_3_2_20_2","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1099\/00221287-143-2-405","article-title":"Cloning of Candida albicans genes conferring resistance to azole antifungal agents: characterization of CDR2, a new multidrug ABC transporter gene","volume":"143","author":"Sanglard D.","year":"1997","unstructured":"Sanglard D. Ischer F. Monod M. Bille J. Cloning of Candida albicans genes conferring resistance to azole antifungal agents: characterization of CDR2, a new multidrug ABC transporter gene.Microbiology1431997405416","journal-title":"Microbiology"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.39.11.2378"},{"key":"e_1_3_2_22_2","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1073\/pnas.95.3.1331","article-title":"mtDNA recombination in a natural population","volume":"95","author":"Saville B. J.","year":"1998","unstructured":"Saville B. J. Kohli Y. Anderson J. B. mtDNA recombination in a natural population.Proc. Natl. Acad. Sci. USA95199813311335","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1128\/mr.54.3.226-241.1990"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1128\/jcm.25.4.675-679.1987"},{"key":"e_1_3_2_25_2","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.1073\/pnas.85.5.1452","article-title":"A Candida albicans dispersed, repeated gene family and its epidemiologic applications","volume":"85","author":"Scherer S.","year":"1988","unstructured":"Scherer S. Stevens D. A. A Candida albicans dispersed, repeated gene family and its epidemiologic applications.Proc. Natl. Acad. Sci. USA85198814521456","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"e_1_3_2_26_2","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1093\/oxfordjournals.molbev.a025633","article-title":"Molecular biology and evolution of resistance to toxicants","volume":"13","author":"Taylor M.","year":"1996","unstructured":"Taylor M. Feyereisen R. Molecular biology and evolution of resistance to toxicants.Mol. Biol. Evol.131996719734","journal-title":"Mol. Biol. Evol."},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.7809610"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.11.2.382"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.285.5426.422"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1128\/jcm.33.9.2476-2479.1995"},{"key":"e_1_3_2_31_2","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1111\/j.1558-5646.1982.tb05065.x","article-title":"Character change, speciation, and the higher taxa","volume":"36","author":"Wright S.","year":"1982","unstructured":"Wright S. Character change, speciation, and the higher taxa.Evolution361982427443","journal-title":"Evolution"},{"key":"e_1_3_2_32_2","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1086\/284777","article-title":"Surfaces of selective value revisited","volume":"131","author":"Wright S.","year":"1988","unstructured":"Wright S. Surfaces of selective value revisited.Am. Nat.1311988115123","journal-title":"Am. Nat."},{"key":"e_1_3_2_33_2","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/41312","article-title":"The advantage of sex in evolving yeast populations","volume":"388","author":"Zeyl C.","year":"1997","unstructured":"Zeyl C. Bell G. The advantage of sex in evolving yeast populations.Nature3881997465468","journal-title":"Nature"}],"container-title":["Journal of Bacteriology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/JB.182.6.1515-1522.2000","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/JB.182.6.1515-1522.2000","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T17:56:40Z","timestamp":1627581400000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/JB.182.6.1515-1522.2000"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2000,3,15]]},"references-count":32,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2000,3,15]]}},"alternative-id":["10.1128\/JB.182.6.1515-1522.2000"],"URL":"https:\/\/doi.org\/10.1128\/jb.182.6.1515-1522.2000","relation":{},"ISSN":["0021-9193","1098-5530"],"issn-type":[{"value":"0021-9193","type":"print"},{"value":"1098-5530","type":"electronic"}],"subject":[],"published":{"date-parts":[[2000,3,15]]},"assertion":[{"value":"1999-09-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"1999-12-21","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-12-20","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}