scholarly journals 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

2006 ◽  
Vol 50 (9) ◽  
pp. 3160-3161 ◽  
Author(s):  
David A. Stevens ◽  
Masayuki Ichinomiya ◽  
Yukako Koshi ◽  
Hiroyuki Horiuchi
Keyword(s):  
Cell Wall ◽  
Paradoxical Effect ◽  
Synthesis Inhibition ◽  
Paradoxical Growth ◽  
Presence And Absence ◽  
Glucan Synthesis ◽  
Rapid Shift

ABSTRACT 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. β-1,3-Glucan declined 81% in the presence of caspofungin, as expected. β-1,6-Glucan declined 73%. Chitin increased 898%, demonstrating a mechanism for paradoxical growth—a rapid shift in the key polymer.

Recent Status and Advancements in the Development of Antifungal Agents: Highlights on Plant and Marine Based Antifungals

2019 ◽  
Vol 19 (10) ◽  
pp. 812-830 ◽  
Author(s):  
P. Marie Arockianathan ◽  
Monika Mishra ◽  
Rituraj Niranjan
Keyword(s):  
Cell Wall ◽  
Antifungal Agents ◽  
Fungal Diseases ◽  
Fungal Cell Wall ◽  
Fungal Resistance ◽  
Ergosterol Biosynthesis ◽  
Fungal Cell ◽  
Ergosterol Synthesis ◽  
Glucan Synthesis ◽  
Anti Fungal

The developing resistance in fungi has become a key challenge, which is being faced nowadays with the available antifungal agents in the market. Further search for novel compounds from different sources has been explored to meet this problem. The current review describes and highlights recent advancement in the antifungal drug aspects from plant and marine based sources. The current available antifungal agents act on specific targets on the fungal cell wall, like ergosterol synthesis, chitin biosynthesis, sphingolipid synthesis, glucan synthesis etc. We discuss some of the important anti-fungal agents like azole, polyene and allylamine classes that inhibit the ergosterol biosynthesis. Echinocandins inhibit β-1, 3 glucan synthesis in the fungal cell wall. The antifungals poloxins and nikkomycins inhibit fungal cell wall component chitin. Apart from these classes of drugs, several combinatorial therapies have been carried out to treat diseases due to fungal resistance. Recently, many antifungal agents derived from plant and marine sources showed potent activity. The renewed interest in plant and marine derived compounds for the fungal diseases created a new way to treat these resistant strains which are evident from the numerous literature publications in the recent years. Moreover, the compounds derived from both plant and marine sources showed promising results against fungal diseases. Altogether, this review article discusses the current antifungal agents and highlights the plant and marine based compounds as a potential promising antifungal agents.

scholarly journals Genomic Approach to Identification of Mutations Affecting Caspofungin Susceptibility in Saccharomyces cerevisiae

2004 ◽  
Vol 48 (10) ◽  
pp. 3871-3876 ◽  
Author(s):  
Sarit Markovich ◽  
Aya Yekutiel ◽  
Itamar Shalit ◽  
Yona Shadkchan ◽  
Nir Osherov
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cell Wall ◽  
Ergosterol Biosynthesis ◽  
Membrane Function ◽  
Minimum Effective Concentration ◽  
Fourfold Increase ◽  
Microdilution Method ◽  
New Genes ◽  
Broth Microdilution Method ◽  
Glucan Synthesis

ABSTRACT The antifungal agent caspofungin (CAS) specifically interferes with glucan synthesis and cell wall formation. To further study the cellular processes affected by CAS, we analyzed a Saccharomyces cerevisiae mutant collection (4,787 individual knockout mutations) to identify new genes affecting susceptibility to the drug. This collection was screened for increased CAS sensitivity (CAS-IS) or increased CAS resistance (CAS-IR). MICs were determined by the broth microdilution method. Disruption of 20 genes led to CAS-IS (four- to eightfold reductions in the MIC). Eleven of the 20 genes are involved in cell wall and membrane function, notably in the protein kinase C (PKC) integrity pathway (MID2, FKS1, SMI1, and BCK1), chitin and mannan biosynthesis (CHS3, CHS4, CHS7, and MNN10), and ergosterol biosynthesis (ERG5 and ERG6). Four of the 20 genes (TPO1, VPS65, VPS25, and CHC1) are involved in vacuole and transport functions, 3 of the 20 genes (CCR4, POP2, and NPL3) are involved in the control of transcription, and 2 of the 20 genes are of unknown function. Disruption of nine additional genes led to CAS-IR (a fourfold increase of MIC). Five of these nine genes (SLG1, ERG3, VRP1, CSG2, and CKA2) are involved in cell wall function and signal transduction, and two of the nine genes (VPS67 and SAC2) are involved in vacuole function. To assess the specificity of susceptibility to CAS, the MICs of amphotericin B, fluconazole, flucytosine, and calcofluor for the strains were tested. Seven of 20 CAS-IS strains (with disruption of FKS1, SMI1, BCK1, CHS4, ERG5, TPO1, and ILM1) and 1 of 9 CAS-IR strains (with disruption of SLG1) demonstrated selective susceptibility to CAS. To further explore the importance of PKC in CAS susceptibility, the activity of the PKC inhibitor staurosporine in combination with CAS was tested against eight Aspergillus clinical isolates by the microdilution assay. Synergistic or synergistic-to-additive activities were found against all eight isolates by use of both MIC and minimum effective concentration endpoints.

scholarly journals Paradoxical Effect of Caspofungin: Reduced Activity against Candida albicans at High Drug Concentrations

2004 ◽  
Vol 48 (9) ◽  
pp. 3407-3411 ◽  
Author(s):  
David A. Stevens ◽  
Marife Espiritu ◽  
Rachana Parmar
Keyword(s):  
Candida Albicans ◽  
Resistance Mechanisms ◽  
Paradoxical Effect ◽  
Fungal Cell ◽  
High Drug ◽  
Minimum Fungicidal Concentration ◽  
Drug Concentrations ◽  
High Concentrations ◽  
Glucan Synthesis

ABSTRACT Resistance problems with caspofungin, an echinocandin inhibitor of fungal cell wall glucan synthesis, have been rare. We noted paradoxical turbid growth of Candida albicans isolates in broth in some high (supra-MIC) concentrations. Among isolates submitted for susceptibility testing and screened at drug concentrations up to 12.5 μg/ml, the frequency was 16%. Analysis of the turbid growth indicated slowing of growth in the presence of drug but with numbers of CFU up to 72% those of drug-free controls. Clearing of growth again by the highest drug concentrations produced a quadriphasic pattern in a tube dilution series. Cells growing at high drug concentrations were not resistant on retesting but showed the paradoxical effect of the parent. Among a selected series of isolates tested at concentrations up to 50 μg/ml, an additional 53% showed a “mini-paradoxical effect”: no turbid growth but incomplete killing at high concentrations (supra-minimum fungicidal concentration). These effects were reproducible; medium dependent in extent; noted in macro- and microdilution, in the presence or absence of serum, and on agar containing drug (but not when drug concentrations were not constant, as in agar diffusion); not seen with other echinocandins and less commonly in other Candida species; and not due to destruction of drug in tubes showing the effect. Cooperative enhancement of inhibition by a second drug could eradicate the effect. We postulate that high drug concentrations derepress or activate resistance mechanisms. The abilities of subpopulations to survive at high drug concentrations could have in vivo consequences.

scholarly journals Transcriptional Regulation of Chitin Synthases by Calcineurin Controls Paradoxical Growth of Aspergillus fumigatus in Response to Caspofungin

2010 ◽  
Vol 54 (4) ◽  
pp. 1555-1563 ◽  
Author(s):  
Jarrod R. Fortwendel ◽  
Praveen R. Juvvadi ◽  
B. Zachary Perfect ◽  
Luise E. Rogg ◽  
John R. Perfect ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Molecular Mechanisms ◽  
Laboratory Strain ◽  
Chitin Synthase ◽  
High Dose ◽  
Paradoxical Effect ◽  
Paradoxical Response ◽  
Paradoxical Growth ◽  
High Concentrations ◽  
Calcineurin Signaling

ABSTRACT Attenuated activity of echinocandin antifungals at high concentrations, known as the “paradoxical effect,” is a well-established phenomenon in Candida albicans and Aspergillus fumigatus. In the yeast C. albicans, upregulation of chitin biosynthesis via the protein kinase C (PKC), high-osmolarity glycerol response (HOG), and Ca2+/calcineurin signaling pathways is an important cell wall stress response that permits growth in the presence of high concentrations of echinocandins. However, nothing is known of the molecular mechanisms regulating the mold A. fumigatus and its paradoxical response to echinocandins. Here, we show that the laboratory strain of A. fumigatus and five of seven clinical A. fumigatus isolates tested display various magnitudes of paradoxical growth in response to caspofungin. Interestingly, none of the eight strains showed paradoxical growth in the presence of micafungin or anidulafungin. Treatment of the ΔcnaA and ΔcrzA strains, harboring gene deletions of the calcineurin A subunit and the calcineurin-dependent transcription factor, respectively, with high concentrations of caspofungin revealed that the A. fumigatus paradoxical effect is calcineurin pathway dependent. Exploring a molecular role for CnaA in the compensatory chitin biosynthetic response, we found that caspofungin treatment resulted in increased chitin synthase gene expression, leading to a calcineurin-dependent increase in chitin synthase activity. Taken together, our data suggest a mechanistic role for A. fumigatus calcineurin signaling in the chitin biosynthetic response observed during paradoxical growth in the presence of high-dose caspofungin treatment.

The yeast KRE5 gene encodes a probable endoplasmic reticulum protein required for (1----6)-beta-D-glucan synthesis and normal cell growth

1990 ◽  
Vol 10 (6) ◽  
pp. 3013-3019
Author(s):  
P Meaden ◽  
K Hill ◽  
J Wagner ◽  
D Slipetz ◽  
S S Sommer ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Wall ◽  
Cell Growth ◽  
Normal Cell ◽  
Secretory Pathway ◽  
Endoplasmic Reticulum Retention Signal ◽  
Endoplasmic Reticulum Protein ◽  
Glucan Synthesis ◽  
Retention Signal ◽  
Sequential Assembly

Yeast kre mutants define a pathway of cell wall (1----6)-beta-D-glucan synthesis, and mutants in genes KRE5 and KRE6 appear to interact early in such a pathway. We have cloned KRE5, and the sequence predicts the product to be a large, hydrophilic, secretory glycoprotein which contains the COOH-terminal endoplasmic reticulum retention signal, HDEL. Deletion of the KRE5 gene resulted in cells with aberrant morphology and extremely compromised growth. Suppressors to the KRE5 deletions arose at a frequency of 1 in 10(7) to 1 in 10(8) and permitted an analysis of deletions which were found to contain no alkali-insoluble (1----6)-beta-D-glucan. These results indicate a role for (1----6)-beta-D-glucan in normal cell growth and suggest a model for sequential assembly of (1----6)-beta-D-glucan in the yeast secretory pathway.

scholarly journals The Lag Period in Auxin-Induced Expansion of Storage Tissue and Coleoptiles

1957 ◽  
Vol 10 (4) ◽  
pp. 435 ◽  
Author(s):  
Heather Adamson ◽  
D Adamson
Keyword(s):  
Cell Wall ◽  
Storage Tissue ◽  
Lag Period ◽  
Rapid Shift

Auxin caused a rapid shift in the point of incipient plasmolysis of a number: of tissues which showed auxin-induced expansion. The plasmolysis shift was not caused by dilution of the cell sap and might be due to an effect of auxin on the adhesion between cytoplasm and cell wall.

scholarly journals Yeast Mycocins: a great potential for application in health

2020 ◽  
Vol 20 (3) ◽  
Author(s):  
Bruna L Nascimento ◽  
Mateus F Delabeneta ◽  
Lana Rubia B Rosseto ◽  
Daniele S B Junges ◽  
Ana Paula Paris ◽  
...  
Keyword(s):  
Cell Wall ◽  
Clinical Practice ◽  
Mechanism Of Action ◽  
Extracellular Proteins ◽  
Main Mechanism ◽  
Minimal Toxicity ◽  
Glucan Synthesis ◽  
Epidemiological Markers

ABSTRACT Mycocins have demonstrated inhibition of fungi, bacteria, parasites and viruses, in addition to being studied as epidemiological markers and in the development of vaccines. They are defined as extracellular proteins or glycoproteins with different activities, the main mechanism of action being the inhibition of β-glucan synthesis in the cell wall of sensitive strains. Given the resistance problems created by several microorganisms to agents commonly used in clinical practice, the discovery of new substances with this purpose becomes essential. Mycocins have potential as anti-microbials because they show minimal toxicity and do not present resistance.

scholarly journals Echinocandins for the Treatment of Invasive Aspergillosis: from Laboratory to Bedside

2019 ◽  
Vol 63 (8) ◽  
Author(s):  
Marion Aruanno ◽  
Emmanouil Glampedakis ◽  
Frédéric Lamoth
Keyword(s):  
Invasive Aspergillosis ◽  
Fungal Infections ◽  
Heat Shock Protein 90 ◽  
Hyphal Growth ◽  
Content Type ◽  
Complex Interactions ◽  
Drug Classes ◽  
Paradoxical Growth ◽  
Glucan Synthesis

ABSTRACT Echinocandins (caspofungin, micafungin, anidulafungin), targeting β-1,3-glucan synthesis of the cell wall, represent one of the three currently available antifungal drug classes for the treatment of invasive fungal infections. Despite their limited antifungal activity against Aspergillus spp., echinocandins are considered an alternative option for the treatment of invasive aspergillosis (IA). This drug class exhibits several advantages, such as excellent tolerability and its potential for synergistic interactions with some other antifungals. The objective of this review is to discuss the in vitro and clinical efficacy of echinocandins against Aspergillus spp., considering the complex interactions between the drug, the mold, and the host. The antifungal effect of echinocandins is not limited to direct inhibition of hyphal growth but also induces an immunomodulatory effect on the host’s response. Moreover, Aspergillus spp. have developed important adaptive mechanisms of tolerance to survive and overcome the action of echinocandins, such as paradoxical growth at increased concentrations. This stress response can be abolished by several compounds that potentiate the activity of echinocandins, such as drugs targeting the heat shock protein 90 (Hsp90)-calcineurin axis, opening perspectives for adjuvant therapies. Finally, the present and future places of echinocandins as prophylaxis, monotherapy, or combination therapy of IA are discussed in view of the emergence of pan-azole resistance among Aspergillus fumigatus isolates, the occurrence of breakthrough IA, and the advent of new long-lasting echinocandins (rezafungin) or other β-1,3-glucan synthase inhibitors (ibrexafungerp).

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