Lipid Biosynthesis as an Antifungal Target

Abstract

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.

Phospholipid homeostasis plays an important role in fungal development, fungicide resistance and virulence in Fusarium graminearum

“…More importantly, Cho1 and Opi3 (ChoC) do not have homologs in mammalian cells. Therefore, new drugs targeting Cho1 and Opi3 could potentially be developed for antifungal therapy or fungal disease control (Pan et al 2018). In agreement with this concept, 7-chloro-N-(4-propylphenyl)-4-quinolinamine (7CPQA) has been shown to reduce Plasmodium yoelii infection in mice, with low toxicity towards mammalian cells, via the inhibition of PSD activity.…”

“…Cells use~5% of their genes to synthesize lipids for cell viability, suggesting the complexity and importance of lipids (Sud et al 2007;Van Meer et al 2008). Because of this complexity and the differences in lipid biosynthetic and metabolic pathways between fungal and mammalian cells, the key enzymes in these pathways have been suggested to be targets of fungicides (Pan et al 2018). For instance, azoles, polyene macrolides and other inhibitors have been developed to interfere with ergosterol biosynthesis to suppress fungal infection (Ghannoum and Rice 1999).…”

Candida auris: multi-omics signature of an emerging and multidrug-resistant pathogen

“…The differential abundance of carbon metabolism, especially in the pyruvate metabolism, is indicative that the fatty acid biosynthesis and consequently the lipid structures could be altered. Considering that lipids are major targets of antifungal drugs (36) and part of resistance mechanisms (37, 38), we analyzed this category of biomolecules. A total of 169 lipids from 10 different classes were identified and quantified.…”

Genome-scale model of Rhodotorula toruloides metabolism

“…A better understanding of lipid metabolism in R. toruloides has applications beyond the production of lipids for fuel and nutraceuticals. R. toruloides has also been used in screens for novel anti-obesity drugs against candidates (Lee, Cheon, & Rhee, 2018), while lipid synthesis has been shown to be a promising target for antifungal therapies (Pan, Hu, & Yu, 2018). Several species within the Rhodotorula genus 50 have been identified as emerging pathogens in both animals and people (Wirth & Goldani, 2012), and intracellular glycerol accumulation caused by hydrolysis of storage triglycerides by pathogenic fungi has been shown to play a crucial role in turgor generation for penetration and invasion of tissues (Nguyen et al, 2011;C.…”