Increases in
            <i>SLT2</i>
            Expression and Chitin Content Are Associated with Incomplete Killing of
            <i>Candida glabrata</i>
            by Caspofungin

Cota, Jason M.; Grabinski, Jodi L.; Talbert, Robert L.; Burgess, David S.; Rogers, P. David; Edlind, Thomas D.; Wiederhold, Nathan P.

doi:10.1128/aac.01542-07

Cited by 66 publications

(71 citation statements)

References 25 publications

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“…In contrast, in mice that received higher doses of caspofungin, the Candida cells within the kidneys had a distorted appearance. This observation is consistent with previous reports of changes in cell morphology in Candida species exposed to echinocandins in vitro and may reflect changes in cell wall architecture due to deficiencies in (133)-␤-D-glucan levels (4, 38), as well as increases in cell wall chitin, which has been reported to occur in Candida species in response to echinocandin exposure (8,21,28,32). In contrast, no dose of caspofungin resulted in improvements in survival or reductions in fungal burden in mice infected with 43001, the more virulent of the resistant isolates in our study.…”

Section: Discussionsupporting

confidence: 82%

Caspofungin Dose Escalation for Invasive Candidiasis Due to Resistant Candida albicans

Wiederhold

Najvar

Bocanegra

et al. 2011

Antimicrob Agents Chemother

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Previous in vivo studies have reported caspofungin dose escalation to be effective against Candida glabrata with reduced susceptibility. We hypothesized that higher doses of caspofungin would be effective against invasive candidiasis caused by the more virulent species Candida albicans, including isolates resistant to this echinocandin. Immunocompetent mice were inoculated with one of three C. albicans isolates, including one susceptible and two resistant isolates with different FKS1 hot spot 1 point mutations. Mice received daily caspofungin treatment for 7 days and were then followed off therapy for 2 weeks to assess survival. Kidney tissue and blood were collected, and fungal burden and serum (133) survival). In contrast, caspofungin doses as low as 1 mg/kg improved survival (85 to 95%) and reduced tissue burden and (133)-␤-D-glucan concentration against the susceptible isolate (ATCC 90028). These data suggest that caspofungin dose escalation for invasive candidiasis may not be consistently effective against resistant C. albicans isolates, and this may be associated with the virulence of the strain.Echinocandins are safe and effective for the treatment of invasive candidiasis. In clinical trials at approved doses, these agents have been shown to have response rates of between 70 and 75% (15,20,25,26). Overall, the toxicity profile of these agents is quite favorable, with reported adverse event rates similar to that of fluconazole and lower than those of amphotericin B formulations (15,20,29). In fact, a recent study demonstrated that daily doses of caspofungin of 150 mg, or three times the recommended daily dose of 50 mg, were safe and well tolerated (3). Similarly, high doses of micafungin have also been shown to be relatively well tolerated, with few toxicities in different patient populations, including patients with hematologic malignancies undergoing stem cell transplantation and children (12,30,31).As is common with most antimicrobials, isolates of different fungal species have developed resistance to echinocandins.

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Section: Discussionsupporting

confidence: 82%

Caspofungin Dose Escalation for Invasive Candidiasis Due to Resistant Candida albicans

Wiederhold

Najvar

Bocanegra

et al. 2011

Antimicrob Agents Chemother

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“…8A), indicating that cells respond to drug exposure by elevating the expression of its target enzyme and a MAPK. CgSLT2 has previously been reported to be transcriptionally up-regulated in response to an echinocandin drug, caspofungin (51). A 2-fold increase in CgFKS2 expression levels in both WT and Cgbem2⌬ upon fluconazole exposure was also observed (data not shown).…”

Section: Cgbem2 Is Required For Activation Of Multidrug Efflux Pumps mentioning

confidence: 49%

The Rho1 GTPase-activating Protein CgBem2 Is Required for Survival of Azole Stress in Candida glabrata

Borah¹,

Shivarathri

Kaur

2011

Journal of Biological Chemistry

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Invasive fungal infections are common clinical complications of neonates, critically ill, and immunocompromised patients worldwide. Candida species are the leading cause of disseminated fungal infections, with Candida albicans being the most prevalent species. Candida glabrata, the second/third most common cause of candidemia, shows reduced susceptibility to a widely used antifungal drug fluconazole. Here, we present findings from a screen of 9134 C. glabrata Tn7 insertion mutants for altered survival profiles in the presence of fluconazole. We have identified two components of RNA polymerase II mediator complex, three players of Rho GTPase-mediated signaling cascade, and two proteins implicated in actin cytoskeleton biogenesis and ergosterol biosynthesis that are required to sustain viability during fluconazole stress. We show that exposure to fluconazole leads to activation of the protein kinase C (PKC)-mediated cell wall integrity pathway in C. glabrata. Our data demonstrate that disruption of a RhoGAP (GTPase activating protein) domain-containing protein, CgBem2, results in budemergence defects, azole susceptibility, and constitutive activation of CgRho1-regulated CgPkc1 signaling cascade and cell wall-related phenotypes. The viability loss of Cgbem2⌬ mutant upon fluconazole treatment could be partially rescued by the PKC inhibitor staurosporine. Additionally, we present evidence that CgBEM2 is required for the transcriptional activation of genes encoding multidrug efflux pumps in response to fluconazole exposure. Last, we report that Hsp90 inhibitor geldanamycin renders fluconazole a fungicidal drug in C. glabrata.

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“…This wall reinforcement in response to various stresses is a well-described phenomenon in fungi (12,(58)(59)(60)(61). While chitin is only a minor constituent of the cell wall, a small increase in the percentage of chitin leads to a more robust wall.…”

Section: Discussionmentioning

confidence: 99%

Surface Stress Induces a Conserved Cell Wall Stress Response in the Pathogenic Fungus Candida albicans

et al. 2013

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cThe human fungal pathogen Candida albicans can grow at temperatures of up to 45°C. Here, we show that at 42°C substantially less biomass was formed than at 37°C. The cells also became more sensitive to wall-perturbing compounds, and the wall chitin levels increased, changes that are indicative of wall stress. Quantitative mass spectrometry of the wall proteome using 15 N metabolically labeled wall proteins as internal standards revealed that at 42°C the levels of the ␤-glucan transglycosylases Phr1 and Phr2, the predicted chitin transglycosylases Crh11 and Utr2, and the wall maintenance protein Ecm33 increased. Consistent with our previous results for fluconazole stress, this suggests that a wall-remodeling response is mounted to relieve wall stress. Thermal stress as well as different wall and membrane stressors led to an increased phosphorylation of the mitogen-activated protein (MAP) kinase Mkc1, suggesting activation of the cell wall integrity (CWI) pathway. Furthermore, all wall and membrane stresses tested resulted in diminished cell separation. This was accompanied by decreased secretion of the major chitinase Cht3 and the endoglucanase Eng1 into the medium. Consistent with this, cht3 cells showed a similar phenotype. When treated with exogenous chitinase, cell clusters both from stressed cells and mutant strains were dispersed, underlining the importance of Cht3 for cell separation. We propose that surface stresses lead to a conserved cell wall remodeling response that is mainly governed by Mkc1 and is characterized by chitin reinforcement of the wall and the expression of remedial wall remodeling enzymes.

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Increases in SLT2 Expression and Chitin Content Are Associated with Incomplete Killing of Candida glabrata by Caspofungin

Cited by 66 publications

References 25 publications

Caspofungin Dose Escalation for Invasive Candidiasis Due to Resistant Candida albicans

Caspofungin Dose Escalation for Invasive Candidiasis Due to Resistant Candida albicans

The Rho1 GTPase-activating Protein CgBem2 Is Required for Survival of Azole Stress in Candida glabrata

Surface Stress Induces a Conserved Cell Wall Stress Response in the Pathogenic Fungus Candida albicans

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