Insights into the modulatory effect of magnesium on efflux mechanisms of Candida albicans reveal inhibition of ATP binding cassette multidrug transporters and dysfunctional mitochondria

Hans, Sandeep; Fatima, Zeeshan; Hameed, Saif

doi:10.1007/s10534-020-00282-w

Cited by 4 publications

(7 citation statements)

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“…Moreover, it mediates a variety of other functions, including sensing and signalling to the outer environment (Kodedová et al, 2019). While Mg homeostasis is an important virulence determinant in C. albicans (Hans et al, 2019(Hans et al, , 2021, the effect of Mg availability on the lipidome of this important human pathogen remains unexplored. Hence, the present study aimed to get deeper insights and comprehend the membrane dynamics in response to Mg deprivation with the application of high-throughput MS-based lipidomics approach.…”

Section: Discussionmentioning

confidence: 99%

“…albicans to varied environmental niches inside the host cells such as micronutrient availability confers the basis of infectivity. In the previous studies, to evaluate the impact of Mg deprivation on drug susceptibilities of membrane targeting drugs, we unravelled the disturbance of membrane homeostasis (Hans et al, 2019) and efflux pump activities (Hans et al, 2021). The role of lipids in the Candida pathogenesis in the context of MDR acquisition has already gained prominence (Prasad & Singh, 2013; Rizzo et al, 2019; Shevchenko & Simons, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…The cells were freshly revived on YPD broth and moved to agar plate before each experiment. To establish Mg deprivation, we used CDTA at a concentration 150 µg/ml that does not substantially inhibit the growth of Candida cells as determined previously (Hans et al, 2019(Hans et al, , 2021 for lipid and RNA isolation along with subsequent biochemical and phenotypic studies.…”

Section: Candida Strain and Growth Conditionsmentioning

confidence: 99%

“…The previous study has demonstrated that Mg deprivation disrupts homeostasis of membrane in C. albicans and the activity of membrane targeting drugs was enhanced (Hans et al, 2019). Additionally, the effect of Mg deprivation on efflux mechanisms of C. albicans revealed inhibition of ATPbinding cassette multidrug transporters and dysfunctional mitochondria (Hans et al, 2021). Taking clue from these previous observations, the current investigation utilized the MS-based lipidomics approach to elaborate our understanding on membrane dynamics, and exposed various lipid-associated changes under Mg deprivation that could be exploited in C. albicans infection treatment strategies.…”

Section: Introductionmentioning

confidence: 95%

“…Additionally, the effect of Mg deprivation on efflux mechanisms of C . albicans revealed inhibition of ATP‐binding cassette multidrug transporters and dysfunctional mitochondria (Hans et al, 2021). Taking clue from these previous observations, the current investigation utilized the MS‐based lipidomics approach to elaborate our understanding on membrane dynamics, and exposed various lipid‐associated changes under Mg deprivation that could be exploited in C .…”

Section: Introductionmentioning

confidence: 99%

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Mass spectrometry‐based untargeted lipidomics reveals new compositional insights into membrane dynamics of Candida albicans under magnesium deprivation

Hans

Fatima

Hameed

2021

J of Applied Microbiology

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There is growing appreciation in adopting new approaches to disrupt multidrug resistance in human fungal pathogen, Candida albicans. The plasma membrane of C. albicans comprises potential lipid moieties that contribute towards the survival of pathogen and could be utilized as antifungal targets. Considering promising applications of developments in mass spectrometry (MS)-based lipidomics technology, the aim of the study was to analyse lipidome profile and expose lipid-dependent changes in response to Mg deprivation. Methods and Results:We found that both phosphatidylcholine (PC) and lysophosphatidylcholine (LysoPC) were decreased. Increased flip (inward translocation) in the fluorophore labelled NBD-PC was ascribed to enhanced PC-specific flippase activity. Furthermore, a decrease in phosphatidylethanolamine (PE) leading to altered membrane fluidity and loss of cellular material was prominent. Additionally, we observed decreased phosphatidylglycerol (PG) and phosphatidylinositol (PI) leading to genotoxic stress. Besides, we could detect enhanced levels of phosphatidylserine (PS), diacylglycerol (DAG) and triacylglycerides (TAG). The altered gene expressions of lipid biosynthetic pathway by RT-PCR correlated with the lipidome profile. Lastly, we explored abrogated ionic (Na + and K + ) transport across the plasma membrane. Conclusions:We propose that C. albicans exposed to Mg deprivation could reorganize plasma membrane (lipid species, membrane fluidity and ionic transport), and possibly redirected carbon flux to store energy in TAGs as an adaptive stress response. This work unravels several vulnerable targets governing lipid metabolism in C. albicans and pave way for better antifungal strategies.Significance and Impact of the study: This study demonstrates that magnesium availability is important when one considers dissecting drug resistance mechanisms in Candida albicans. Through mass spectrometry (MS)-based lipidomics technology, the study analyses lipidome profile and exposes lipid-dependent changes that are vulnerable to magnesium availability and presents an opportunity to employ this new information in improving treatment strategies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Candida Strain and Growth Conditionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Mass spectrometry‐based untargeted lipidomics reveals new compositional insights into membrane dynamics of Candida albicans under magnesium deprivation

Hans

Fatima

Hameed

2021

J of Applied Microbiology

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Metal Chelation as a Promising Strategy to Combat Fungal Drug Resistance

Hans¹,

Fatima²,

Hameed³

2023

Non-Traditional Approaches to Combat Antimicrobial Drug Resistance

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Magnesium impairs Candida albicans immune evasion by reduced hyphal damage, enhanced β-glucan exposure and altered vacuole homeostasis

et al. 2022

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With a limited arsenal of available antifungal drugs and drug-resistance emergence, strategies that seek to reduce Candida immune evasion and virulence could be a promising alternative option. Harnessing metal homeostasis against C. albicans has gained wide prominence nowadays as a feasible antifungal strategy. Herein, the effect of magnesium (Mg) deprivation on the immune evasion mechanisms of C. albicans is demonstrated. We studied host pathogen interaction by using the THP-1 cell line model and explored the avenue that macrophage-mediated killing was enhanced under Mg deprivation, leading to altered cytokine (TNFα, IL-6 and IL10) production and reduced pyroptosis. Insights into the mechanisms revealed that hyphal damage inside the macrophage was diminished under Mg deprivation. Additionally, Mg deprivation led to cell wall remodelling; leading to enhanced β-1,3-glucan exposure, crucial for immune recognition, along with concomitant alterations in chitin and mannan levels. Furthermore, vacuole homeostasis was disrupted under Mg deprivation, as revealed by abrogated morphology and defective acidification of the vacuole lumen. Together, we demonstrated that Mg deprivation affected immune evasion mechanisms by: reduced hyphal damage, enhanced β-1,3-glucan exposure and altered vacuole functioning. The study establishes that Mg availability is indispensable for successful C. albicans immune evasion and specific Mg dependent pathways could be targeted for therapy.

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Insights into the modulatory effect of magnesium on efflux mechanisms of Candida albicans reveal inhibition of ATP binding cassette multidrug transporters and dysfunctional mitochondria

Cited by 4 publications

References 35 publications

Mass spectrometry‐based untargeted lipidomics reveals new compositional insights into membrane dynamics of Candida albicans under magnesium deprivation

Mass spectrometry‐based untargeted lipidomics reveals new compositional insights into membrane dynamics of Candida albicans under magnesium deprivation

Metal Chelation as a Promising Strategy to Combat Fungal Drug Resistance

Magnesium impairs Candida albicans immune evasion by reduced hyphal damage, enhanced β-glucan exposure and altered vacuole homeostasis

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