Deletion of the Ca
            <i>BIG1</i>
            Gene Reduces β-1,6-Glucan Synthesis, Filamentation, Adhesion, and Virulence in
            <i>Candida albicans</i>

Umeyama, Takashi; Kaneko, Aki; Watanabe, Hiroshi; Hirai, Ayako; Uehara, Yoshimasa; Niimi, Masakazu; Azuma, Masayuki

doi:10.1128/iai.74.4.2373-2381.2006

Cited by 41 publications

(23 citation statements)

References 32 publications

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“…Therefore, a ␤-1,6-glucan inhibitor is expected to remove these proteins from the cell and reduce the pathogenesis of C. albicans as a result. In fact, there are several reports suggesting that C. albicans mutants with a reduced level of ␤-1,6-glucan are avirulent (16,45). Our study clearly shows a potent inhibitory effect of D75-4590 against hyphal elongation as well.…”

Section: Discussionsupporting

confidence: 65%

“…[ 14 C]glucose (Daiichi Pure Chemicals, Tokyo, Japan) was added to a cell suspension at a concentration of 2 Ci/ml. At each time point, a 10-ml sample was taken and crude fractions of ␤-1,3-glucan, chitin, mannan, and ␤-1,6-glucan were prepared based on the method of Umeyama et al (45). The harvested cells were suspended in 2 ml of 3% NaOH and heated for 1 h at 80°C.…”

Section: Strainsmentioning

confidence: 99%

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Discovery of a Small-Molecule Inhibitor of β-1,6-Glucan Synthesis

Kitamura

Someya

Hata

et al. 2009

Antimicrob Agents Chemother

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It is possible that antifungal drugs with novel modes of action will provide favorable options to treat fungal infections. In the course of our screening for antifungal compounds acting on the cell wall, a pyridobenzimidazole derivative with unique activities, named D75-4590, was discovered. During treatment of Saccharomyces cerevisiae with D75-4590, (i) incorporation of [ 14 C]glucose into the ␤-1,6-glucan component was selectively reduced, (ii) proteins released from the cell had lost the ␤-1,6-glucan moiety, and (iii) cells tended to clump, resulting in impaired cell growth. Genetic analysis of a D75-4590-resistant mutant of S. cerevisiae indicated that its primary target was Kre6p, which is considered to be one of the ␤-1,6-glucan synthases. These results strongly suggest that D75-4590 is a specific inhibitor of ␤-1,6-glucan synthesis. D75-4590 showed potent activities against various Candida species. It inhibited hyphal elongation of C. albicans as well. KRE6 is conserved in various fungi, but no homologue has been found in mammalian cells. These lines of evidence indicate that D75-4590 is a promising lead compound for novel antifungal drugs. To our knowledge, this is the first report of a ␤-1,6-glucan inhibitor.

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Section: Discussionsupporting

confidence: 65%

Section: Strainsmentioning

confidence: 99%

Discovery of a Small-Molecule Inhibitor of β-1,6-Glucan Synthesis

Kitamura

Someya

Hata

et al. 2009

Antimicrob Agents Chemother

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“…Taken together, our study demonstrated that Spf1 is essential for maintenance of cellular calcium homeostasis under ER stresses and high-level calcium conditions. In C. albicans, hyphal cells contain more chitin and b-1,6-glucan, and less mannoproteins than yeast cells, indicating a link between hyphal development and cell wall composition, which is dependent on cell wall protein homeostasis (Herrero et al, 2004;Umeyama et al, 2006). Our study showed that the spf1D/D mutant had a significant defect in hyphal development.…”

Section: Role Of Spf1 In Candida Albicansmentioning

confidence: 61%

Spf1 strongly influences calcium homeostasis, hyphal development, biofilm formation and virulence in Candida albicans

Wang

et al. 2012

Microbiology

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The maintenance of cellular calcium homeostasis is associated with cellular signalling transduction and the functions of many membrane compartments, especially endoplasmic reticulum (ER) function. ER-localized proteins that serve to maintain ER and cellular calcium homeostasis in Candida albicans are still unclear. In this study, Spf1, the putative C. albicans homologue of the Saccharomyces cerevisiae ER-localized P-type calcium ATPase ScSpf1, was investigated for its roles in cellular calcium homeostasis, hyphal development and virulence. We constructed an Spf1 null mutant which showed decreased vegetative growth rate and hypersensitivity to EGTA, high-level calcium and antifungal drugs. Similar to treatments of ER stress agents, deletion of SPF1 stimulated calcium influx in the presence of FK506, resulting in an increase in cellular calcium contents, and induced expression of the calcium-dependent response elements gene CCH1, which is essential for the cell calcium survival pathway. Moreover, the spf1 null mutant had defects in hyphal development and biofilm formation, and was severely attenuated in virulence. These findings provided phenotypic evidence supporting roles for Spf1 in the maintenance of cellular calcium homeostasis, ER stress responses, hyphal development, biofilm formation and virulence in C. albicans.

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“…␤-1,6-Glucan synthesis and incorporation proceed through several enzyme steps (14), and Fks1p inhibition would affect a late stage. Our finding is consistent with suggestions from gene disruption studies (6) and studies of glucose linkages in Cryptococcus neoformans (7) and broadens our understanding of caspofungin antifungal mechanisms.…”

mentioning

confidence: 99%

Escape of Candida from Caspofungin Inhibition at Concentrations above the MIC (Paradoxical Effect) Accomplished by Increased Cell Wall Chitin; Evidence for β-1,6-Glucan Synthesis Inhibition by Caspofungin

Stevens

Ichinomiya

Koshi

et al. 2006

Antimicrob Agents Chemother

180

136

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Concentrations above the MIC of caspofungin allow growth of some Candida isolates. A strain demonstrating paradoxical growth was grown in the presence and absence of caspofungin, and the cell wall content was analyzed. ␤-1,3-Glucan declined 81% in the presence of caspofungin, as expected. ␤-1,6-Glucan declined 73%. Chitin increased 898%, demonstrating a mechanism for paradoxical growth-a rapid shift in the key polymer.

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Deletion of the Ca BIG1 Gene Reduces β-1,6-Glucan Synthesis, Filamentation, Adhesion, and Virulence in Candida albicans

Cited by 41 publications

References 32 publications

Discovery of a Small-Molecule Inhibitor of β-1,6-Glucan Synthesis

Discovery of a Small-Molecule Inhibitor of β-1,6-Glucan Synthesis

Spf1 strongly influences calcium homeostasis, hyphal development, biofilm formation and virulence in Candida albicans

Escape of Candida from Caspofungin Inhibition at Concentrations above the MIC (Paradoxical Effect) Accomplished by Increased Cell Wall Chitin; Evidence for β-1,6-Glucan Synthesis Inhibition by Caspofungin

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