Dimorphism-associated changes in plasma membrane H+-ATPase activity of Candida albicans

Kaur, Simminder; Mishra, Prashant

doi:10.1007/bf00248719

Cited by 14 publications

(14 citation statements)

References 35 publications

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“…In C. albicans , optimum pH has been implicated in various virulence pathways involving a dimorphic switch and proteinases and lipases secretion (Patenaude et al, 2013 ; Raines et al, 2013 ). As the primary regulator of cytosolic pH, Pma1 could affect the dimorphic transition, which is essential for the host invasion and tissue damage (Kaur and Mishra, 1991 ; Seto-Young et al, 1997 ). Simminder Kaur et al reported that C. albicans failed to form germ tubes and hyphae in the presence of Pma1 inhibitor orthovanadate (Kaur et al, 1988 ; Stewart et al, 1989 ).…”

Section: H + Homeostasis and Potential Antifungal mentioning

confidence: 99%

Promising Antifungal Targets Against Candida albicans Based on Ion Homeostasis

Sun²,

et al. 2018

Front. Cell. Infect. Microbiol.

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In recent decades, invasive fungal infections have been increasing significantly, contributing to high incidences and mortality in immunosuppressed patients. Candida albicans (C. albicans) is the most prevalent opportunistic fungal pathogen in humans that can cause severe and often fatal bloodstream infections. Current antifungal agents have several limitations, including that only a small number of classes of antifungals are available, certain of which have severe toxicity and high cost. Moreover, the emergence of drug resistance is a new limitation to successful patient outcomes. Therefore, the development of antifungals with novel targets is an essential strategy for the efficient management of C. albicans infections. It is widely recognized that ion homeostasis is crucial for all living cells. Many studies have identified that ion-signaling and transduction networks are central to fungal survival by regulating gene expression, morphological transition, host invasion, stress response, and drug resistance. Dysregulation of ion homeostasis rapidly mediates cell death, forming the mechanistic basis of a growing number of compounds that elicit antifungal activity. Most of the potent antifungals have been widely used in the clinic, and certain of them have low toxicity, meaning that they may be expected to be used as antifungal drugs in the future. Hence, we briefly summarize the homeostasis regulation of several important ions, potential antifungal targets based on these ion-signaling networks, and antifungal compounds based on the disruption of ion homeostasis. This summary will help in designing effective drugs and identifying new targets for combating fungal diseases.

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Section: H + Homeostasis and Potential Antifungal mentioning

confidence: 99%

Promising Antifungal Targets Against Candida albicans Based on Ion Homeostasis

Sun²,

et al. 2018

Front. Cell. Infect. Microbiol.

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“…In fungi, cytosolic pH is regulated via the Pma1p plasma membrane proton transporter, which pumps protons out of the cell and into the extracellular space to maintain a neutral-to-alkaline cytosol and an acidic extracellular environment (Monk et al, 1991). The importance of Pma1p activity and cytosolic alkalinization in C. albicans virulence is illustrated by studies showing that Pma1p activity and expression is upregulated during filamentation (Kaur and Mishra, 1991; Monk et al, 1993). Furthermore, C. albicans mutants that cannot properly alkalinize their cytosol in response to filamentation cues are avirulent (Stewart et al, 1988, 1989; Mahanty et al, 1990).…”

Section: Candida Albicans Pathogenicity Correlates With Ph Regulationmentioning

confidence: 99%

Advances in targeting the vacuolar proton-translocating ATPase (V-ATPase) for anti-fungal therapy

2014

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Vacuolar proton-translocating ATPase (V-ATPase) is a membrane-bound, multi-subunit enzyme that uses the energy of ATP hydrolysis to pump protons across membranes. V-ATPase activity is critical for pH homeostasis and organelle acidification as well as for generation of the membrane potential that drives secondary transporters and cellular metabolism. V-ATPase is highly conserved across species and is best characterized in the model fungus Saccharomyces cerevisiae. However, recent studies in mammals have identified significant alterations from fungi, particularly in the isoform composition of the 14 subunits and in the regulation of complex disassembly. These differences could be exploited for selectivity between fungi and humans and highlight the potential for V-ATPase as an anti-fungal drug target. Candida albicans is a major human fungal pathogen and causes fatality in 35% of systemic infections, even with anti-fungal treatment. The pathogenicity of C. albicans correlates with environmental, vacuolar, and cytoplasmic pH regulation, and V-ATPase appears to play a fundamental role in each of these processes. Genetic loss of V-ATPase in pathogenic fungi leads to defective virulence, and a comprehensive picture of the mechanisms involved is emerging. Recent studies have explored the practical utility of V-ATPase as an anti-fungal drug target in C. albicans, including pharmacological inhibition, azole therapy, and targeting of downstream pathways. This overview will discuss these studies as well as hypothetical ways to target V-ATPase and novel high-throughput methods for use in future drug discovery screens.

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“…In addition, envisaging an initial near neutral pHi (pHi can remain stable at high pH; Rabaste et al, 1995), the transmembrane pH gradient could reverse a putative Cl--OH-exchanger, resulting in further medium acidification. The existence of a C1-exchanger has already been proposed to explain discrepancies between PM H+-ATPase activity and rates of pHi change (Kaur & Mishra, 1991). Increasing external C1-would reduce the magnitude of the outwardly directed C1-gradient pertinent to both putative anion transporters and reduce their rates, thus reducing in turn both pump-and exchanger-mediated acidification rates.…”

Section: Effect Of Na+ and Anions On Acidification Ratesmentioning

confidence: 99%

Influence of Na+ and anions on the dimorphic transition of Candida albicans

1997

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The effect of Na+ (CI' or gluconate salt) on growth and dimorphic potential of the pathogenic yeast Candida albicans has been examined. Profiles of germ tube formation as a function of salt addition, pH and temperature indicated Na+ inhibition of germ tube outgrowth at high ambient pH (pH 8 0 ) which was exacerbated by replacement of CI' with gluconate (as an impermeant analogue). At acidic pH (pH 5 5 ) and permissive temperature (37 "C), gluconate alone promoted the dimorphic transition. Rates of glucose-induced medium acidification and plasma membrane H+-ATPase activity have been measured to assess whether salt treatments could retard the cytoplasmic alkalinization known to precede germ tube formation. The precise site of Na+ action remains unclear but the anion effects may be interpreted in terms of anion-exchanger and channel activity acting to modulate cytosolic pH.

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Dimorphism-associated changes in plasma membrane H+-ATPase activity of Candida albicans

Cited by 14 publications

References 35 publications

Promising Antifungal Targets Against Candida albicans Based on Ion Homeostasis

Promising Antifungal Targets Against Candida albicans Based on Ion Homeostasis

Advances in targeting the vacuolar proton-translocating ATPase (V-ATPase) for anti-fungal therapy

Influence of Na+ and anions on the dimorphic transition of Candida albicans

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