Chromosome 5 of Human Pathogen Candida albicans Carries Multiple Genes for Negative Control of Caspofungin and Anidulafungin Susceptibility

Suwunnakorn, Sumanun; Wakabayashi, Hironao; Rustchenko, Elena

doi:10.1128/aac.01888-16

Cited by 25 publications

(35 citation statements)

References 31 publications

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“…We found a good correspondence between the two methods, as expected (22,23,26), as all caspofungin-tolerant mutants exhibited better growth than that of the strains with parental disomic or duplicated Ch5 (see data for one representative series in Fig. 5 and for all 3 series in Fig.…”

Section: Figsupporting

confidence: 76%

“…In contrast, strains with a duplicated Ch5 and control strains had levels of chitin or glucan similar to the levels in the parental strains (22). Many of these mutants also acquired tolerance to caspofungin, which we now explain as being due to a diminished gene dose of at least three Ch5-carried genes, PGA4, CHT2, and CSU51, which encode negative regulators of caspofungin susceptibility (23).…”

mentioning

confidence: 72%

“…This is consistent with the better growth of the tolerant mutants on agar-based plates shown in Fig. 4. to sorbose (22) or to caspofungin (23). Apparently, CHT2 is downregulated in all kinds of mutants (Table 1).…”

Section: Figmentioning

confidence: 92%

“…We believe that multiple genes are regulated in concert in order to increase the amount of chitin. This regulation may include, for example, the downregulation of CHT2, PGA4, and CSU51 on the monosomic Ch5 that we recently found in caspofungin-generated mutants (23) (Table 1), as well as upregulation of CHS2 and CHS3 for the chitin synthases encoded outside Ch5 (34).…”

Section: Fig 8 Map Of Ch5mentioning

confidence: 94%

“…The final number of Ch5 genes for negative regulation of caspofungin susceptibility has yet to be determined (23). We previously showed that CHT2, PGA4, and CSU51 are downregulated on the monosomic Ch5 but not on the spontaneously reduplicated Ch5 (23) (see Table 1 for CHT2 data).…”

Section: Fig 8 Map Of Ch5mentioning

confidence: 99%

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Tolerance to Caspofungin in Candida albicans Is Associated with at Least Three Distinctive Mechanisms That Govern Expression of FKS Genes and Cell Wall Remodeling

Yang

Zhang

Wakabayashi

et al. 2017

Antimicrob Agents Chemother

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Expanding echinocandin use to prevent or treat invasive fungal infections has led to an increase in the number of breakthrough infections due to resistant Candida species. Although it is uncommon, echinocandin resistance is well documented for Candida 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 aneuploidyindependent mechanism. Tolerant mutants possessed cell walls with elevated chitin and showed downregulation of genes involved in cell wall biosynthesis, namely, FKS, located outside Ch5, and CHT2, located on Ch5, irrespective of Ch5 ploidy. Also irrespective of Ch5 ploidy, the CNB1 and MID1 genes 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 of FKS1 have previously been associated with caspofungin resistance, we found mechanisms of caspofungin tolerance that are independent of FKS1 and thus represent an earlier event in resistance development.

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Section: Figsupporting

confidence: 76%

mentioning

confidence: 72%

Section: Figmentioning

confidence: 92%

Section: Fig 8 Map Of Ch5mentioning

confidence: 94%

Section: Fig 8 Map Of Ch5mentioning

confidence: 99%

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Tolerance to Caspofungin in Candida albicans Is Associated with at Least Three Distinctive Mechanisms That Govern Expression of FKS Genes and Cell Wall Remodeling

Yang

Zhang

Wakabayashi

et al. 2017

Antimicrob Agents Chemother

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CSU57 encodes a novel repressor of sorbose utilization in opportunistic human fungal pathogen Candida albicans

Reddy

Pullepu

Dhabalia

et al. 2020

Yeast

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Human fungal pathogen Candida albicans cannot utilize L‐sorbose as a sole carbon source. However, chromosome 5 monosomic strains can grow on sorbose as repressors present on this chromosome get diminished allowing the expression of sorbose utilization gene (SOU1) located on chromosome 4. Functional identification of these repressors has been a difficult task as they are scattered on a large portion of the right arm of chromosome 5. Herein, we have applied the telomere‐mediated chromosomal truncation approach to identify a novel repressor for sorbose utilization in this pathogen. Multiple systematic chromosomal truncations were performed on the right arm of Chr5 in the background of csu51∆/CSU51 to minimize the functional region to 6‐kb chromosomal stretch. Further, truncation that removes the part of Orf19.3942 strongly suggested its role in sorbose utilization. However, compelling evidence comes from the observation that truncation at 1,044.288‐kb position of Chr5 in the strain csu51∆/CSU51 orf19.3942∆/Orf.19.3942 produced Sou+ phenotype; otherwise, the strain remains Sou−. This confirms beyond doubt the role of Orf.19.3942 in the regulation of sorbose utilization and designated as CSU57. Comparison of SOU1 gene expression of Sou+ strains with wild type suggested its role at transcriptional level. Strain carrying double disruption of CSU57 remains Sou−. Co‐overexpression of SOU1 and CSU57 together does not make the recipient strain Sou−; however, multiple tandem copies of CSU57 produced diminished growth compared with control suggesting that it is a weak repressor. Taken together, we report that CSU57 encodes a novel repressor of L‐sorbose utilization in this pathogen. TAKE AWAY CSU57 encodes a repressor for L‐sorbose utilization in Candida albicans. Csu57p acts in combination with Csu51p and other regulators. Csu57p exerts its repressing effect at transcriptional level of SOU1 gene. Utilization of sorbose positively correlates to the expression of SOU1 gene. Multiple copies of CSU57 can partially suppress Sou+ phenotype.

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Genome plasticity in Candida albicans: A cutting-edge strategy for evolution, adaptation, and survival

Elibe

Nweze

Eze

et al. 2022

Infection, Genetics and Evolution

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Chromosome 5 of Human Pathogen Candida albicans Carries Multiple Genes for Negative Control of Caspofungin and Anidulafungin Susceptibility

Cited by 25 publications

References 31 publications

Tolerance to Caspofungin in Candida albicans Is Associated with at Least Three Distinctive Mechanisms That Govern Expression of FKS Genes and Cell Wall Remodeling

Tolerance to Caspofungin in Candida albicans Is Associated with at Least Three Distinctive Mechanisms That Govern Expression of FKS Genes and Cell Wall Remodeling

CSU57 encodes a novel repressor of sorbose utilization in opportunistic human fungal pathogen Candida albicans

Genome plasticity in Candida albicans: A cutting-edge strategy for evolution, adaptation, and survival

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