Oxygen accessibility and iron levels are critical factors for the antifungal action of ciclopirox against Candida albicans

Sigle, H C; Thewes, Sascha; Niewerth, M.; Körting, Hans Christian; Schäfer‐Korting, Monika; Hube, Bernhard

doi:10.1093/jac/dki089

Cited by 50 publications

(47 citation statements)

References 27 publications

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“…5). This is in agreement with the observation that the antifungal agent ciclopirox, which is believed to possess iron-chelating properties as well, strongly increases the transcript level of RBT5 (Lee et al, 2005;Sigle et al, 2005). Interestingly, the presence of ferrozine in the medium also caused an increase in the cell wall of the adhesion protein Fig.…”

Section: Discussionsupporting

confidence: 90%

Hypoxic conditions and iron restriction affect the cell-wall proteome of Candida albicans grown under vagina-simulative conditions

et al. 2008

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Proteins that are covalently linked to the skeletal polysaccharides of the cell wall of Candida albicans play a major role in the colonization of the vaginal mucosal surface, which may result in vaginitis. Here we report on the variability of the cell-wall proteome of C. albicans as a function of the ambient O 2 concentration and iron availability. For these studies, cells were cultured at 37 6C in vagina-simulative medium and aerated with a gas mixture consisting of 6 % (v/v) CO 2 , 0.01-7 % (v/v) O 2 and N 2 , reflecting the gas composition in the vaginal environment. Under these conditions, the cells grew exclusively in the non-hyphal form, with the relative growth rate being halved at~0.02 % (v/v) O 2 . Using tandem MS and immunoblot analysis, we identified 15 covalently linked glycosylphosphatidylinositol (GPI) proteins in isolated walls (Als1, Als3, Cht2, Crh11, Ecm33, Hwp1, Pga4, Pga10, Phr2, Rbt5, Rhd3, Sod4, Ssr1, Ywp1, Utr2) and 4 covalently linked non-GPI proteins (MP65, Pir1, Sim1/Sun42, Tos1). Five of them (Als3, Hwp1, Sim1, Tos1, Utr2) were absent in cells grown in rich medium. Immunoblot analysis revealed that restricted O 2 availability resulted in higher levels of the non-GPI protein Pir1, a putative b-1,3-glucan cross-linking protein, and of the GPI-proteins Hwp1, an adhesion protein, and Pga10 and Rbt5, which are involved in iron acquisition. Addition of the iron chelator ferrozine at saturating levels of O 2 resulted in higher cell wall levels of Hwp1 and Rbt5, suggesting that the responses to hypoxic conditions and iron restriction are related. INTRODUCTIONCandida albicans is a pleiomorphic pathogenic fungus that is responsible for many mucosal infections in humans, and may cause systemic, often fatal infections in immunocompromised patients (Calderone, 2002). It is also well equipped to form biofilms on abiotic surfaces such as dentures and medical devices (Blankenship & Mitchell, 2006;Ramage et al., 2006). Covalently linked cell-wall proteins (CWPs) play an important role in initiating and maintaining mucosal infections and biofilms Li et al., 2007;Naglik et al., 2006;Nobile et al., 2006;Richard & Plaine, 2007;Ruiz-Herrera et al., 2006;Sundstrom, 1999;Zhao et al., 2006;Zupancic & Cormack, 2007). This is consistent with their cellular location because covalently linked CWPs form an external protein layer surrounding the internal skeletal polysaccharide layer of the wall, and thus come directly into contact with biotic and abiotic surfaces. As in Saccharomyces cerevisiae, the cell-wall proteome of C. albicans consists of 15 or more covalently linked CWPs and includes structural proteins, adhesion proteins, carbohydrate-active proteins, proteases, superoxide dismutases and iron-acquisition proteins (Albrecht et al., 2006; De Groot et al., 2004;Garcera et al., 2005;Mao et al., 2003;Weissman & Kornitzer, 2004). In agreement with the outcome of similar studies carried out with S. cerevisiae, genomic transcript profiling studies of C. albicans indicate that the composition of the cell-wall proteo...

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Section: Discussionsupporting

confidence: 90%

Hypoxic conditions and iron restriction affect the cell-wall proteome of Candida albicans grown under vagina-simulative conditions

et al. 2008

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“…As Als3 also functions as a ferritin receptor (Almeida et al, 2008), the observed increase in Als3 levels could also be related to iron starvation. (iii) Consistent with the transcriptional data obtained from iron-starved cells (Chen et al, 2011;Sigle et al, 2005), the wall levels of the GPImodified superoxide dismutase Sod4 increased 11-and 42-fold in BPS-16 and BPS-26 cultures, respectively, compared to the control, whereas Sod5 levels slightly decreased. However, this is in contrast to the strongly increased wall levels of Sod5 and the decreased levels of Sod4 in hyphal cultures observed under various hyphal-growthinducing conditions (Heilmann et al, 2011;Martchenko et al, 2004).…”

Section: Resultssupporting

confidence: 86%

“…They are also regulated by the transcription factor Sef1, which is the major activator of iron uptake genes, and as for RBT5 family members, direct binding of Sef1 to the regulatory region of SOD4 could be shown (Chen et al, 2011). Interestingly, the expression of the RBT5 family members was also strongly increased in the presence of the antifungal drug ciclopirox olamine, which is believed to induce iron starvation (Lee et al, 2005;Sigle et al, 2005). Similar results were obtained for the monoclonal antibody C7 that is proposed to exert its candidacidal activity by blockage of the reductive iron uptake system (Brena et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Iron restriction-induced adaptations in the wall proteome of Candida albicans

et al. 2013

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The opportunistic fungal pathogen Candida albicans has developed various ways to overcome iron restriction in a mammalian host. Using different surface proteins, among them membrane-and wall-localized glycosylphosphatidylinositol (GPI) proteins, it can exploit iron from host haemoglobin, ferritin and transferrin. Culturing C. albicans in rich medium supplemented with the ferrous iron chelator bathophenanthroline disulfonic acid or in the minimal medium yeast nitrogen base resulted in a strong decrease of the iron content of the cells. MS analysis of the changes in the wall proteome of C. albicans upon iron restriction showed a strong increase in the levels of the GPI-modified adhesin Als3, which also serves as a ferritin receptor, and of the GPI-modified CFEM (common in fungal extracellular membranes) domain-containing proteins Csa1, Pga7, Pga10, and Rbt5. The wall levels of the GPI-modified proteins Hyr1, the adhesin Als4 and the copper-and zinc-containing superoxide dismutase Sod4 also strongly increased, whereas the levels of Tos1 (a non-GPI protein) and the GPI-modified adhesin Als2 strongly decreased. Strikingly, peptides derived from the CFEM domain of the haem-binding proteins Csa1, Pga10 and Rbt5 were capable of forming iron adduct ions during MS analysis, consistent with a key role of this domain in haem binding.

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“…Information about coding sequences and proteins was obtained from the CandidaDB database (http://genolist.pasteur.fr/CandidaDB/). RNA was reverse transcribed into cDNA and labelled with Cy3 or Cy5 (dye swap) (Sigle et al, 2005). Labelled cDNA was hybridized to the C. albicans arrays as described by Sigle et al (2005).…”

Section: Disruption Of Caplc1mentioning

confidence: 99%

“…RNA was reverse transcribed into cDNA and labelled with Cy3 or Cy5 (dye swap) (Sigle et al, 2005). Labelled cDNA was hybridized to the C. albicans arrays as described by Sigle et al (2005). Hybridized slides were scanned with an Axon 4000B scanner at a 10 mm resolution.…”

Section: Disruption Of Caplc1mentioning

confidence: 99%

Functional analysis of the phospholipase C gene CaPLC1 and two unusual phospholipase C genes, CaPLC2 and CaPLC3, of Candida albicans

et al. 2005

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Phospholipases C are known to be important regulators of cellular processes but may also act as virulence factors of pathogenic microbes. At least three genes in the genome of the human-pathogenic fungus Candida albicans encode phospholipases with conserved phospholipase C (Plc) motifs. None of the deduced protein sequences contain N-terminal signal peptides, suggesting that these phospholipases are not secreted. In contrast to its orthologue in Sacharomyces cerevisiae, CaPLC1 seems to be an essential gene. However, a conditional mutant with reduced transcript levels of CaPLC1 had phenotypes similar to Plc1p-deficient mutants in S. cerevisiae, including reduced growth on media causing increased osmotic stress, on media with a non-glucose carbon source, or at elevated or lower temperatures, suggesting that CaPlc1p, like the Plc1p counterpart in S. cerevisiae, may be involved in multiple cellular processes. Furthermore, phenotypic screening of the heterozygous ΔCaplc1/CaPLC1 mutant showed additional defects in hyphal formation. The loss of CaPLC1 cannot be compensated by two additional PLC genes of C. albicans (CaPLC2 and CaPLC3) encoding two almost identical phospholipases C with no counterpart in S. cerevisiae but containing structural elements found in bacterial phospholipases C. Although the promoter sequences of CaPLC2 and CaPLC3 differed dramatically, the transcriptional pattern of both genes was similar. In contrast to CaPLC1, CaPLC2 and CaPLC3 are not essential. Although Caplc2/3 mutants had reduced abilities to produce hyphae on solid media, these mutants were as virulent as the wild-type in a model of systemic infection. These data suggest that C. albicans contains two different classes of phospholipases C which are involved in cellular processes but which have no specific functions in pathogenicity.

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Oxygen accessibility and iron levels are critical factors for the antifungal action of ciclopirox against Candida albicans

Abstract: These data indicate that metabolic activity, oxygen accessibility and iron levels are critical parameters in the mode of action of ciclopirox olamine.

Cited by 50 publications

References 27 publications

Hypoxic conditions and iron restriction affect the cell-wall proteome of Candida albicans grown under vagina-simulative conditions

Hypoxic conditions and iron restriction affect the cell-wall proteome of Candida albicans grown under vagina-simulative conditions

Iron restriction-induced adaptations in the wall proteome of Candida albicans

Functional analysis of the phospholipase C gene CaPLC1 and two unusual phospholipase C genes, CaPLC2 and CaPLC3, of Candida albicans

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