title: Tolerance to Caspofungin in Candida albicans Is Associated with at Least Three Distinctive Mechanisms That Govern Expression ofFKSGenes and Cell Wall Remodeling.
abstract: Expanding echinocandin use to prevent or treat invasive fungal infections has led to an increase in the number of breakthrough infections due to resistantCandidaspecies. Although it is uncommon, echinocandin resistance is well documented forCandida albicans, which is among the most prevalent bloodstream organisms. A better understanding is needed to assess the cellular factors that promote tolerance and predispose infecting cells to clinical breakthrough. We previously showed that some mutants that were adapted to growth in the presence of toxic sorbose due to loss of one chromosome 5 (Ch5) also became more tolerant to caspofungin. We found here, following direct selection of mutants on caspofungin, that tolerance can be conferred by at least three mechanisms: (i) monosomy of Ch5, (ii) combined monosomy of the left arm and trisomy of the right arm of Ch5, and (iii) an aneuploidy-independent mechanism. Tolerant mutants possessed cell walls with elevated chitin and showed downregulation of genes involved in cell wall biosynthesis, namely,FKS, located outside Ch5, andCHT2, located on Ch5, irrespective of Ch5 ploidy. Also irrespective of Ch5 ploidy, theCNB1andMID1genes on Ch5, which are involved in the calcineurin signaling pathway, were expressed at the diploid level. Thus, multiple mechanisms can affect the relative expression of the aforementioned genes, controlling them in similar ways. Although breakthrough mutations in two specific regions ofFKS1have previously been associated with caspofungin resistance, we found mechanisms of caspofungin tolerance that are independent ofFKS1and thus represent an earlier event in resistance development.
authors.affiliation: Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Yang
authors.affiliation: Center for New Drug Research, School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Lulu
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Hironao
authors.initials: H
authors.lastname: Wakabayashi
authors.affiliation: Genomic Research Center, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Myers
authors.affiliation: Center for New Drug Research, School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Yuanying
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Center for New Drug Research, School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China ybcao@vip.sina.com elena_bulgac@urmc.rochester.edu.
authors.forename: Yongbing
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, New Jersey, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Jimenez-Ortigosa
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, New Jersey, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Perlin
authors.affiliation: Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, New York, USA ybcao@vip.sina.com elena_bulgac@urmc.rochester.edu.
authors.forename: Elena
authors.initials: E
authors.lastname: Rustchenko
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D019703:Calcineurin / Q000378:metabolism; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics* / Q000254:growth & development / Q000302:isolation & purification; D000077336:Caspofungin; D002473:Cell Wall / Q000378:metabolism*; D002686:Chitin / Q000378:metabolism; D002688:Chitinases / Q000235:genetics; D025141:Drug Resistance, Fungal / Q000235:genetics*; D054714:Echinocandins / Q000494:pharmacology*; D006801:Humans; D055666:Lipopeptides / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000235:genetics*; D008826:Microbial Sensitivity Tests; D047071:beta-Glucans / Q000378:metabolism*
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D008562:Membrane Glycoproteins; D047071:beta-Glucans; D002686:Chitin; D019703:Calcineurin; D002688:Chitinases; D000077336:Caspofungin
keywords: Candida albicans; caspofungin tolerance; chromosome 5; molecular mechanisms