PS, It’s Complicated: The Roles of Phosphatidylserine and Phosphatidylethanolamine in the Pathogenesis of Candida albicans and Other Microbial Pathogens

Cassilly, Chelsi D.; Reynolds, Todd B.

doi:10.3390/jof4010028

Cited by 55 publications

(37 citation statements)

References 110 publications

(131 reference statements)

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“…One related peptide exhibits antifungal activity against Candida albicans and Trichosporon beigelii [ 40 ]. It should be noted that PS plays a relevant role in both cancer development [ 35 , 41 , 42 , 43 ] and Candida albicans virulence [ 44 , 45 , 46 , 47 , 48 ] for which PG [ 49 ] and PI [ 47 ] are also important.…”

Section: Resultsmentioning

confidence: 99%

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Antimicrobial Peptide K11 Selectively Recognizes Bacterial Biomimetic Membranes and Acts by Twisting Their Bilayers

et al. 2020

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K11 is a synthetic peptide originating from the introduction of a lysine residue in position 11 within the sequence of a rationally designed antibacterial scaffold. Despite its remarkable antibacterial properties towards many ESKAPE bacteria and its optimal therapeutic index (320), a detailed description of its mechanism of action is missing. As most antimicrobial peptides act by destabilizing the membranes of the target organisms, we investigated the interaction of K11 with biomimetic membranes of various phospholipid compositions by liquid and solid-state NMR. Our data show that K11 can selectively destabilize bacterial biomimetic membranes and torque the surface of their bilayers. The same is observed for membranes containing other negatively charged phospholipids which might suggest additional biological activities. Molecular dynamic simulations reveal that K11 can penetrate the membrane in four steps: after binding to phosphate groups by means of the lysine residue at the N-terminus (anchoring), three couples of lysine residues act subsequently to exert a torque in the membrane (twisting) which allows the insertion of aromatic side chains at both termini (insertion) eventually leading to the flip of the amphipathic helix inside the bilayer core (helix flip and internalization).

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Section: Resultsmentioning

confidence: 99%

“…One member of the K11 SR family also displays activity against fungi like Candida albicans . As shown in this work, K11 targets PS and PI, both being relevant for Candida virulence [ 44 , 45 , 46 , 47 , 48 ], together with PG [ 49 ].…”

Section: Resultsmentioning

confidence: 99%

Antimicrobial Peptide K11 Selectively Recognizes Bacterial Biomimetic Membranes and Acts by Twisting Their Bilayers

et al. 2020

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“…PS synthase (⑩), PS decarboxylase (⑪), and phospholipid methylase (⑬), shown with bold arrows in Figure 3 , have been reported in the literature as potential antifungal targets [ 32 ]. The Candida albicans PS synthase mutant, Δ cho1 , lacking PS, has a decreased PE content and is avirulent in a mouse model of systemic candidiasis.…”

Section: Specific Lipid Metabolism In Fungimentioning

confidence: 99%

Lipid Biosynthesis as an Antifungal Target

Pan

2018

JoF

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Lipids, commonly including phospholipids, sphingolipids, fatty acids, sterols, and triacylglycerols (TAGs), are important biomolecules for the viability of all cells. Phospholipids, sphingolipids, and sterols are important constituents of biological membranes. Many lipids play important roles in the regulation of cell metabolism by acting as signaling molecules. Neutral lipids, including TAGs and sterol esters (STEs), are important storage lipids in cells. In view of the importance of lipid molecules, this review briefly summarizes the metabolic pathways for sterols, phospholipids, sphingolipids, fatty acids, and neutral lipids in fungi and illustrates the differences between fungal and human (or other mammalian) cells, especially in relation to lipid biosynthetic pathways. These differences might provide valuable clues for us to find target proteins for novel antifungal drugs. In addition, the development of lipidomics technology in recent years has supplied us with a shortcut for finding new antifungal drug targets; this ability is important for guiding our research on pathogenic fungi.

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“…The cho1⌬/cho1⌬ null mutant is also viable in C. albicans (15). Interestingly, although the in vitro growth of this mutant can be rescued by addition of ethanolamine, Cho1 is essential for Candida virulence in a murine infection model and has thus been proposed as a potential drug target (15,33). A recent study further demonstrated that the mutant cells might not be able to acquire sufficient ethanolamine from the host, leading to the avirulent phenotype (34).…”

Section: Discussionmentioning

confidence: 99%

Phosphatidylserine synthesis is essential for viability of the human fungal pathogen Cryptococcus neoformans

Konarzewska

Wang

Han

et al. 2019

Journal of Biological Chemistry

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Phospholipids are an integral part of the cellular membrane structure and can be produced by a de novo biosynthetic pathway and, alternatively, by the Kennedy pathway. Studies in several yeast species have shown that the phospholipid phosphatidylserine (PS) is synthesized from CDP-diacylglycerol and serine, a route that is different from its synthesis in mammalian cells, involving a base-exchange reaction from preexisting phospholipids. Fungal-specific PS synthesis has been shown to play an important role in fungal virulence and has been proposed as an attractive drug target. However, PS synthase, which catalyzes this reaction, has not been studied in the human fungal pathogen Cryptococcus neoformans. Here, we identified and characterized the PS synthase homolog (Cn Cho1) in this fungus. Heterologous expression of Cn CHO1 in a Saccharomyces cerevisiae cho1⌬ mutant rescued the mutant's growth defect in the absence of ethanolamine supplementation. Moreover, an Sc cho1⌬ mutant expressing Cn CHO1 had PS synthase activity, confirming that the Cn CHO1 encodes PS synthase. We also found that PS synthase in C. neoformans is localized to the endoplasmic reticulum and that it is essential for mitochondrial function and cell viability. Of note, its deficiency could not be complemented by ethanolamine or choline supplementation for the synthesis of phosphatidylethanolamine (PE) or phosphatidylcholine (PC) via the Kennedy pathway. These findings improve our understanding of phospholipid synthesis in a pathogenic fungus and indicate that PS synthase may be a useful target for antifungal drugs. 2 The abbreviations used are:

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PS, It’s Complicated: The Roles of Phosphatidylserine and Phosphatidylethanolamine in the Pathogenesis of Candida albicans and Other Microbial Pathogens

Cited by 55 publications

References 110 publications

Antimicrobial Peptide K11 Selectively Recognizes Bacterial Biomimetic Membranes and Acts by Twisting Their Bilayers

Antimicrobial Peptide K11 Selectively Recognizes Bacterial Biomimetic Membranes and Acts by Twisting Their Bilayers

Lipid Biosynthesis as an Antifungal Target

Phosphatidylserine synthesis is essential for viability of the human fungal pathogen Cryptococcus neoformans

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