Monoterpenoid perillyl alcohol impairs metabolic flexibility of Candida albicans by inhibiting glyoxylate cycle

Ansari, Moiz A.; Fatima, Zeeshan; Ahmad, Kamal; Hameed, Saif

doi:10.1016/j.bbrc.2017.11.064

Cited by 21 publications

(33 citation statements)

References 24 publications

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“…To check the phenotypic susceptibility under glucose-deprived conditions drop dilution assay was performed as described previously in the absence (control) and presence of THP (Ansari et al 2018). Briefly, 5 µl of fivefold serially diluted yeast cultures (OD 600 0Á1) were spotted onto yeast nitrogen base (TNB) with 2% glycerol, 2% ethanol, 2% sodium citrate and 2% sodium acetate plates.…”

Section: Drop Dilution Assaymentioning

confidence: 99%

“…The I-TASSER predicted model of Icl1p and Mls1p is described as previously reported (Ansari et al 2018). The model optimized using steepest descent method from Auto Dock Tools (ADT) ver.…”

Section: Molecular Dockingmentioning

confidence: 99%

“…The 2D and 3D structures of THP and known inhibitors like 3-nitopropianoate and bromopyruvate were drawn with the help of Chembio Draw ultra. Further calculations and file preparations are performed according to our published protocol (Ahmad et al 2017;Ansari et al 2018). After preparing the coordinate files of Icl1p and Mls1p and THP, it was subjected to docking using Auto-Dock 4.2 package (Morris et al 1998).…”

Section: Molecular Dockingmentioning

confidence: 99%

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Repurposing of respiratory drug theophylline againstCandida albicans: mechanistic insights unveil alterations in membrane properties and metabolic fitness

Singh

Fatima

Ahmad

et al. 2020

J. Appl. Microbiol.

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Aims Drug repurposing is an attractive chemotherapeutic strategy that serves to make up for the inadequacy of current antifungal drugs. The present study aims to repurpose theophylline (THP) against Candida albicans. THP is a methylxanthine derived from cocoa beans and tea extracts, generally used as the first‐line drug for asthma and other respiratory disorders. Methods and Results We investigated the antifungal activity of THP against C. albicans and non‐albicans species. Mechanistic insights revealed that THP induces membrane damage. Enhanced ionic disturbances and depleted ergosterol levels with the concomitant rise in membrane fluidity due to elevated flippase activity confirmed the membrane damaging effect. THP impeded the metabolic adaptability of C. albicans by inhibiting malate synthase and isocitrate lyase enzymes of the glyoxylate cycle. In vivo efficacy of THP was depicted by increased survival of C. albicans infected Caenorhabditis elegans model. Conclusions This study elucidates the antifungal potential of THP with mechanistic insights. Significance and Impact of the Study This study unveils the antifungal potential of THP, a known respiratory drug that can be further utilized for a wider range of applications such as combating fungal infections. The effect of THP with the known antifungal drugs can be exploited in the combinatorial drug approach for treating candidiasis.

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Section: Drop Dilution Assaymentioning

confidence: 99%

“…The I-TASSER predicted model of Icl1p and Mls1p is described as previously reported (Ansari et al 2018). The model optimized using steepest descent method from Auto Dock Tools (ADT) ver.…”

Section: Molecular Dockingmentioning

confidence: 99%

Section: Molecular Dockingmentioning

confidence: 99%

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Repurposing of respiratory drug theophylline againstCandida albicans: mechanistic insights unveil alterations in membrane properties and metabolic fitness

Singh

Fatima

Ahmad

et al. 2020

J. Appl. Microbiol.

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“…The homozygous gsy1 null mutant strain CaMS627 showed no growth retardation in rich media, no grossly abnormal content of neutral lipids (as measured by Nile Red staining), no morphological phenotype and only a slight delay in germ tube induction at 37 °C in YPD with 10% fetal bovine serum. Furthermore, the gsy1/gsy1 mutant had normal survival on solid surfaces on all tested media as well as normal resistance to the glyoxylate cycle inhibitors itaconic acid and perillic alcohol [27,28]. Glycogen content and viability of C. albicans wildtype (WT) SN152 and corresponding efg1/efg1 mutant.…”

Section: Construction and Characterization Of A Glycogen Synthase 1 Mmentioning

confidence: 99%

“…It has been recognized that survival within the host requires C. albicans to have significant metabolic flexibility. And indeed, inhibitors of energy redistribution between lipid and carbohydrate metabolism-glyoxylate cycle inhibitors-have shown potential as antifungal agents [27,28].…”

Section: Glycogen In Yeastmentioning

confidence: 99%

Genetic Regulators and Physiological Significance of Glycogen Storage in Candida albicans

Zeitz

Tanveer

Openshaw

et al. 2019

JoF

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The dimorphic human fungal pathogen C. albicans has broad metabolic flexibility that allows it to adapt to the nutrient conditions in different host habitats. C. albicans builds large carbohydrate stores (glycogen) at the end of exponential growth and begins consumption of stored carbohydrates when nutrients become limiting. The expression of genes required for the successful transition between host environments, including the factors controlling glycogen content, is controlled by protein kinase A signaling through the transcription factor Efg1. In addition to the inability to transition to hyphal growth, C. albicans efg1 mutants have low glycogen content and reduced long-term survival, suggesting that carbohydrate storage is required for viability during prolonged culture. To test this assumption, we constructed a glycogen-deficient C. albicans mutant and assessed its viability during extended culture. Pathways and additional genetic factors controlling C. albicans glycogen synthesis were identified through the screening of mutant libraries for strains with low glycogen content. Finally, a part of the Efg1-regulon was screened for mutants with a shortened long-term survival phenotype. We found that glycogen deficiency does not affect long-term survival, growth, metabolic flexibility or morphology of C. albicans. We conclude that glycogen is not an important contributor to C. albicans fitness.

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Perillyl alcohol and its synthetic derivatives: the rising of a novel class of selective and potent antitumoral compounds

Lessa

Gomes

2022

Med Chem Res

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Monoterpenoid perillyl alcohol impairs metabolic flexibility of Candida albicans by inhibiting glyoxylate cycle

Cited by 21 publications

References 24 publications

Repurposing of respiratory drug theophylline againstCandida albicans: mechanistic insights unveil alterations in membrane properties and metabolic fitness

Repurposing of respiratory drug theophylline againstCandida albicans: mechanistic insights unveil alterations in membrane properties and metabolic fitness

Genetic Regulators and Physiological Significance of Glycogen Storage in Candida albicans

Perillyl alcohol and its synthetic derivatives: the rising of a novel class of selective and potent antitumoral compounds

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