Potential Antifungal Targets Based on Glucose Metabolism Pathways of

Overview

Journal Front Microbiol

Specialty Microbiology

Date 2020 Apr 8

PMID 32256459

Citations 16

Authors

Xueqi Chen

Zewen Zhang

Zuozhong Chen

Yiman Li

Shan Su

Shujuan Sun

Affiliations

Soon will be listed here.

Abstract

In recent years, fungal infections have become a serious health problem. are considered as the fourth most common isolates associated with approximately 40% mortality in bloodstream infections among hospitalized patients. Due to various limitations of classical antifungals used currently, such as limited kinds of drugs, inevitable toxicities, and high price, there is an urgent need to explore new antifungal agents based on novel targets. Generally, nutrient metabolism is involved with fungal virulence, and glucose is one of the important nutrients in . can obtain and metabolize glucose through a variety of pathways; in theory, many enzymes in these pathways can be potential targets for developing new antifungal agents, and several studies have confirmed that compounds which interfere with alpha-glucosidase, acid trehalase, trehalose-6-phosphate synthase, class II fructose bisphosphate aldolases, and glucosamine-6-phosphate synthase in these pathways do have antifungal activities. In this review, the glucose metabolism pathways in , the potential antifungal targets based on these pathways, and some compounds which have antifungal activities by inhibiting several enzymes in these pathways are summarized. We believe that our review will be helpful to the exploration of new antifungal drugs with novel antifungal targets.

Citing Articles

Response of alcohol fermentation strains, mixed fermentation and extremozymes interactions on wine flavor.

Zhao L, Chen J, Wei X, Lin B, Zheng F, Verma K Front Microbiol. 2025; 16:1532539.

PMID: 39944646 PMC: 11813877. DOI: 10.3389/fmicb.2025.1532539.

The Significance of Mono- and Dual-Effective Agents in the Development of New Antifungal Strategies.

Zobi C, Algul O Chem Biol Drug Des. 2025; 105(1):e70045.

PMID: 39841631 PMC: 11753615. DOI: 10.1111/cbdd.70045.

Antifungal and anti-biofilm effects of hydrazone derivatives on spp.

Popczyk P, Ghinet A, Bortolus C, Kamus L, Lensink M, de Ruyck J J Enzyme Inhib Med Chem. 2024; 39(1):2429109.

PMID: 39589067 PMC: 11600518. DOI: 10.1080/14756366.2024.2429109.

The progress and future of the treatment of Candida albicans infections based on nanotechnology.

Gao Y, Cao Q, Xiao Y, Wu Y, Ding L, Huang H J Nanobiotechnology. 2024; 22(1):568.

PMID: 39285480 PMC: 11406819. DOI: 10.1186/s12951-024-02841-6.

Novel targets and improved immunotherapeutic techniques with an emphasis on antimycosal drug resistance for the treatment and management of mycosis.

Adhikary K, Banerjee A, Ganguly K, Sarkar R, Mohanty S, Dhua R Heliyon. 2024; 10(16):e35835.

PMID: 39224344 PMC: 11367498. DOI: 10.1016/j.heliyon.2024.e35835.

References

Mio T, Kokado M, Arisawa M, Yamada-Okabe H . Reduced virulence of Candida albicans mutants lacking the GNA1 gene encoding glucosamine-6-phosphate acetyltransferase. Microbiology (Reading). 2000; 146 ( Pt 7):1753-1758. DOI: 10.1099/00221287-146-7-1753. View

Milewski S, Gabriel I, Olchowy J . Enzymes of UDP-GlcNAc biosynthesis in yeast. Yeast. 2006; 23(1):1-14. DOI: 10.1002/yea.1337. View

Ansari M, Fatima Z, Ahmad K, Hameed S . Monoterpenoid perillyl alcohol impairs metabolic flexibility of Candida albicans by inhibiting glyoxylate cycle. Biochem Biophys Res Commun. 2017; 495(1):560-566. DOI: 10.1016/j.bbrc.2017.11.064. View

Labbe G, Krismanich A, de Groot S, Rasmusson T, Shang M, Brown M . Development of metal-chelating inhibitors for the Class II fructose 1,6-bisphosphate (FBP) aldolase. J Inorg Biochem. 2012; 112:49-58. DOI: 10.1016/j.jinorgbio.2012.02.032. View

de Amorim A, de Lima A, Rosario A, Souza E, Ferreira J, Hage-Melim L . Molecular modeling of inhibitors against fructose bisphosphate aldolase from . In Silico Pharmacol. 2019; 6(1):2. PMC: 6314639. DOI: 10.1007/s40203-018-0040-x. View

Kaur R, Dahiya L, Kumar M . Fructose-1,6-bisphosphatase inhibitors: A new valid approach for management of type 2 diabetes mellitus. Eur J Med Chem. 2017; 141:473-505. DOI: 10.1016/j.ejmech.2017.09.029. View

Pawlak D, Stolarska M, Wojciechowski M, Andruszkiewicz R . Synthesis, anticandidal activity of N(3)-(4-methoxyfumaroyl)-(S)-2,3-diaminopropanoic amide derivatives--novel inhibitors of glucosamine-6-phosphate synthase. Eur J Med Chem. 2014; 90:577-82. DOI: 10.1016/j.ejmech.2014.12.007. View

Bae M, Kim H, Moon K, Nam S, Shin J, Oh K . Mohangamides A and B, new dilactone-tethered pseudo-dimeric peptides inhibiting Candida albicans isocitrate lyase. Org Lett. 2015; 17(3):712-5. DOI: 10.1021/ol5037248. View

Rodaki A, Young T, Brown A . Effects of depleting the essential central metabolic enzyme fructose-1,6-bisphosphate aldolase on the growth and viability of Candida albicans: implications for antifungal drug target discovery. Eukaryot Cell. 2006; 5(8):1371-7. PMC: 1539134. DOI: 10.1128/EC.00115-06. View

10.

Leuker C, Sonneborn A, Delbruck S, Ernst J . Sequence and promoter regulation of the PCK1 gene encoding phosphoenolpyruvate carboxykinase of the fungal pathogen Candida albicans. Gene. 1997; 192(2):235-40. DOI: 10.1016/s0378-1119(97)00069-3. View

11.

Magalhaes R, De Lima K, de Almeida D, De Mesquita J, Eleutherio E . Trehalose-6-Phosphate as a Potential Lead Candidate for the Development of Tps1 Inhibitors: Insights from the Trehalose Biosynthesis Pathway in Diverse Yeast Species. Appl Biochem Biotechnol. 2016; 181(3):914-924. DOI: 10.1007/s12010-016-2258-6. View

12.

Alvarez-Peral F, Zaragoza O, Pedreno Y, Arguelles J . Protective role of trehalose during severe oxidative stress caused by hydrogen peroxide and the adaptive oxidative stress response in Candida albicans. Microbiology (Reading). 2002; 148(Pt 8):2599-2606. DOI: 10.1099/00221287-148-8-2599. View

13.

de Aguiar Cordeiro R, Macedo R, Teixeira C, Marques F, Bandeira T, Moreira J . The calcineurin inhibitor cyclosporin A exhibits synergism with antifungals against Candida parapsilosis species complex. J Med Microbiol. 2014; 63(Pt 7):936-944. DOI: 10.1099/jmm.0.073478-0. View

14.

Jong A, Chen S, Stins M, Kim K, Tuan T, Huang S . Binding of Candida albicans enolase to plasmin(ogen) results in enhanced invasion of human brain microvascular endothelial cells. J Med Microbiol. 2003; 52(Pt 8):615-622. DOI: 10.1099/jmm.0.05060-0. View

15.

Rutherford J, Bahn Y, van den Berg B, Heitman J, Xue C . Nutrient and Stress Sensing in Pathogenic Yeasts. Front Microbiol. 2019; 10:442. PMC: 6423903. DOI: 10.3389/fmicb.2019.00442. View

16.

Lockhart D, Stanley M, Raimi O, Robinson D, Boldovjakova D, Squair D . Targeting a critical step in fungal hexosamine biosynthesis. J Biol Chem. 2020; 295(26):8678-8691. PMC: 7324522. DOI: 10.1074/jbc.RA120.012985. View

17.

Maidan M, De Rop L, Relloso M, Diez-Orejas R, Thevelein J, Van Dijck P . Combined inactivation of the Candida albicans GPR1 and TPS2 genes results in avirulence in a mouse model for systemic infection. Infect Immun. 2008; 76(4):1686-94. PMC: 2292893. DOI: 10.1128/IAI.01497-07. View

18.

Strijbis K, Distel B . Intracellular acetyl unit transport in fungal carbon metabolism. Eukaryot Cell. 2010; 9(12):1809-15. PMC: 3008284. DOI: 10.1128/EC.00172-10. View

19.

Bramono K, Tsuboi R, Ogawa H . A carbohydrate-degrading enzyme from Candida albicans: correlation between alpha-glucosidase activity and fungal growth. Mycoses. 1995; 38(9-10):349-53. DOI: 10.1111/j.1439-0507.1995.tb00063.x. View

20.

Zhang Q, Zhang Y, Zhang P, Chao Z, Xia F, Jiang C . Hexokinase II inhibitor, 3-BrPA induced autophagy by stimulating ROS formation in human breast cancer cells. Genes Cancer. 2014; 5(3-4):100-12. PMC: 4091531. DOI: 10.18632/genesandcancer.9. View