Action Mechanisms of Medicinal Plant Components as Antimycosis: A Literature Review
DOI:
https://doi.org/10.56294/saludcyt20251647Keywords:
Plant active constituents, Mechanism of action, Antifungal activity, Natural products, Sustainable development goals (SDGs), Good health and well-being, Innovation in healthcareAbstract
Mycosis poses a significant threat to global health, particularly in immune-compromised individuals, and the rise of antifungal resistance has further complicated their treatment. The rise in fungal infections (FIs) is a growing concern, contributing significantly to global morbidity and mortality rates. Medicinal plants (MPs), with their long history of use in traditional medicine, have emerged as a valuable source of bioactive compounds with potent antifungal properties. The current study explores the mechanisms by which plant active constituents (PACs) exert their antifungal effects, including inhibition of cell membrane (CM) and cell wall (CW) synthesis, mitochondrial dysfunction, the inhibition of Nucleic acids (Nas) and protein synthesis (PS), inhibiting the electron transport chain, decreasing ATP production, inhibiting glycolysis, oxidative phosphorylation, and oxygen uptake by cells, and this lead to affect cell division, protein production, and /or inhibiting its mycelial growth and spore germination. Compounds such as flavonoids, alkaloids, terpenoids, and other PACs have demonstrated significant antifungal activity through these diverse mechanisms, offering potential alternatives to conventional antifungal drugs. This study highlights the potential of MPs as a foundation for developing novel antifungal therapies. Furthermore, it underscores the importance of understanding the intraocular mechanisms of action (MsOA) to combat antifungal resistance and improve therapeutic outcomes. This comprehensive analysis not only validates the use of MPs in traditional medicine but also provides a roadmap for future research and drug development in the fight against FIs. This study aligns with and supports sustainable development goals (SDGs), including good health and well-being (SDG 3) and other goals.
References
1. Rayens E, Norris KA. Prevalence and Healthcare Burden of Fungal Infections in the United States, 2018. Open Forum Infect Dis. 2022 Jan 10;9(1):ofab593. doi: 10.1093/ofid/ofab593. DOI: https://doi.org/10.1093/ofid/ofab593
2. Howell SA. Dermatopathology and the Diagnosis of Fungal Infections. Br J Biomed Sci. 2023 Jun 7;80:11314. doi: 10.3389/bjbs.2023.11314. DOI: https://doi.org/10.3389/bjbs.2023.11314
3. Vermes A, Guchelaar HJ, Dankert J. Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions. Journal of Antimicrobial Chemotherapy. 2000 Aug 1;46(2):171-9. https://doi.org/10.1093/jac/46.2.171 DOI: https://doi.org/10.1093/jac/46.2.171
4. Aboody MSA, Mickymaray S. Anti-Fungal Efficacy and Mechanisms of Flavonoids. Antibiotics (Basel). 2020 Jan 26;9(2):45. doi: 10.3390/antibiotics9020045. DOI: https://doi.org/10.3390/antibiotics9020045
5. de Oliveira HC, Bezerra BT, Rodrigues ML. Antifungal Development and the Urgency of Minimizing the Impact of Fungal Diseases on Public Health. ACS Bio Med Chem Au. 2022 Nov 18;3(2):137-146. doi: 10.1021/acsbiomedchemau.2c00055. DOI: https://doi.org/10.1021/acsbiomedchemau.2c00055
6. Vaou N, Stavropoulou E, Voidarou C, Tsigalou C, Bezirtzoglou E. Towards Advances in Medicinal Plant Antimicrobial Activity: A Review Study on Challenges and Future Perspectives. Microorganisms. 2021 Sep 27;9(10):2041. doi:10.3390/microorganisms9102041. DOI: https://doi.org/10.3390/microorganisms9102041
7. Santra HK, Banerjee D. Natural Products as Fungicide and Their Role in Crop Protection. Natural Bioactive Products in Sustainable Agriculture. 2020 May 12:131–219. doi: 10.1007/978-981-15-3024-1_9. DOI: https://doi.org/10.1007/978-981-15-3024-1_9
8. Michalak M. Plant-Derived Antioxidants: Significance in Skin Health and the Ageing Process. International Journal of Molecular Sciences. 2022; 23(2):585. https://doi.org/10.3390/ijms23020585 DOI: https://doi.org/10.3390/ijms23020585
9. Mazu TK, Bricker BA, Flores-Rozas H, Ablordeppey SY. The Mechanistic Targets of Antifungal Agents: An Overview. Mini Rev Med Chem. 2016;16(7):555-78. doi: 10.2174/1389557516666160118112103. DOI: https://doi.org/10.2174/1389557516666160118112103
10. Zobi C, Algul O. The Significance of Mono‐and Dual‐Effective Agents in the Development of New Antifungal Strategies. Chemical Biology & Drug Design. 2025 Jan;105(1):e70045. DOI: https://doi.org/10.1111/cbdd.70045
11. Lee Y, Robbins N, Cowen LE. Molecular mechanisms governing antifungal drug resistance. npj Antimicrobials and Resistance. 2023 Jul 17;1(1):5. https://doi.org/10.1038/s44259-023-00007-2 DOI: https://doi.org/10.1038/s44259-023-00007-2
12. Denham ST, Wambaugh MA, Brown JCS. How Environmental Fungi Cause a Range of Clinical Outcomes in Susceptible Hosts. J Mol Biol. 2019 Jul 26;431(16):2982-3009. doi: 10.1016/j.jmb.2019.05.003. DOI: https://doi.org/10.1016/j.jmb.2019.05.003
13. Hossain CM, Ryan LK, Gera M, Choudhuri S, Lyle N, Ali KA, Diamond G. Antifungals and Drug Resistance. Encyclopedia. 2022; 2(4):1722-1737. https://doi.org/10.3390/encyclopedia2040118 DOI: https://doi.org/10.3390/encyclopedia2040118
14. Ivanov M, Ćirić A, Stojković D. Emerging antifungal targets and strategies. International Journal of Molecular Sciences. 2022 Mar 2;23(5):2756. DOI: https://doi.org/10.3390/ijms23052756
15. Denning DW, Bromley M. 2015. How to bolster the antifungal pipeline. Science 347:1414 –1416. https://doi.org/10.1126/science.aaa6097. DOI: https://doi.org/10.1126/science.aaa6097
16. Bugeda A, Garrigues S, Gandía M, Manzanares P, Marcos JF, Coca M. 2020. The antifungal protein AfpB induces regulated cell death in its parental fungus Penicillium digitatum. mSphere 5:e00595-20. https://doi.org/10.1128/mSphere.00595-20. DOI: https://doi.org/10.1128/msphere.00595-20
17. Ghannoum MA, Rice LB. Antifungal agents: mode of action, mechanisms of resistance, and correlation of these mechanisms with bacterial resistance. Clin Microbiol Rev. 1999 Oct;12(4):501-17. doi: 10.1128/CMR.12.4.501. DOI: https://doi.org/10.1128/CMR.12.4.501
18. Prasad R, Shah AH, Rawal MK. Antifungals: Mechanism of Action and Drug Resistance. Adv Exp Med Biol. 2016;892:327-349. doi: 10.1007/978-3-319-25304-6_14. PMID: 26721281. DOI: https://doi.org/10.1007/978-3-319-25304-6_14
19. Fisher MC, Alastruey-Izquierdo A, Berman J, Bicanic T, Bignell EM, Bowyer P, Bromley M, Brüggemann R, Garber G, Cornely OA, Gurr SJ, Harrison TS, Kuijper E, Rhodes J, Sheppard DC, Warris A, White PL, Xu J, Zwaan B, Verweij PE. Tackling the emerging threat of antifungal resistance to human health. Nat Rev Microbiol. 2022 Sep;20(9):557-571. doi: 10.1038/s41579-022-00720-1. DOI: https://doi.org/10.1038/s41579-022-00720-1
20. Zhang CW, Zhong XJ, Zhao YS, Rajoka MS, Hashmi MH, Zhai P, Song X. Antifungal natural products and their derivatives: a review of their activity and mechanism of actions. Pharmacological Research-Modern Chinese Medicine. 2023 Jun 1;7:100262. DOI: https://doi.org/10.1016/j.prmcm.2023.100262
21. Dowling A, O’dwyer J, Adley C. Antibiotics: mode of action and mechanisms of resistance. Antimicrobial research: Novel bioknowledge and educational programs. 2017;1:536-45.
22. Hasim S, Coleman JJ. Targeting the fungal cell wall: current therapies and implications for development of alternative antifungal agents. Future medicinal chemistry. 2019 Apr 1;11(8):869-83. DOI: https://doi.org/10.4155/fmc-2018-0465
23. Osset-Trénor P, Pascual-Ahuir A, Proft M. Fungal Drug Response and Antimicrobial Resistance. Journal of Fungi. 2023 May 12;9(5):565. DOI: https://doi.org/10.3390/jof9050565
24. Hector RF. Compounds active against cell walls of medically important fungi. Clinical microbiology reviews. 1993 Jan;6(1):1-21. DOI: https://doi.org/10.1128/CMR.6.1.1
25. Carolus H, Pierson S, Lagrou K, Van Dijck P. Amphotericin B and other polyenes—discovery, clinical use, mode of action and drug resistance. Journal of Fungi. 2020 Nov 27;6(4):321. DOI: https://doi.org/10.3390/jof6040321
26. Logan A, Wolfe A, Williamson JC. Antifungal resistance and the role of new therapeutic agents. Current Infectious Disease Reports. 2022 Sep;24(9):105-16. DOI: https://doi.org/10.1007/s11908-022-00782-5
27. Hoenigl M, Sprute R, Egger M, Arastehfar A, Cornely OA, Krause R, Lass-Flörl C, Prattes J, Spec A, Thompson GR, Wiederhold N. The antifungal pipeline: fosmanogepix, ibrexafungerp, olorofim, opelconazole, and rezafungin. Drugs. 2021 Oct;81:1703-29. DOI: https://doi.org/10.1007/s40265-021-01611-0
28. Hoenigl M, Sprute R, Arastehfar A, Perfect JR, Lass-Flörl C, Bellmann R, Prattes J, Thompson III GR, Wiederhold NP, Al Obaidi MM, Willinger B. Invasive candidiasis: investigational drugs in the clinical development pipeline and mechanisms of action. Expert opinion on investigational drugs. 2022 Aug 3;31(8):795-812. DOI: https://doi.org/10.1080/13543784.2022.2086120
29. Mueller, S.W.; Kedzior, S.K.; Miller, M.A.; Reynolds, P.M.; Kiser, T.H.; Krsak, M.; Molina, K.C. An overview of current and emerging antifungal pharmacotherapy for invasive fungal infections. Expert Opin. Pharmacother. 2021, 22, 1355–1371. DOI: https://doi.org/10.1080/14656566.2021.1892075
30. Pittet, M.; Conzelmann, A. Biosynthesis and function of GPI proteins in the yeast Saccharomyces cerevisiae. Biochim. Biophys. Acta 2007, 1771, 405–420 DOI: https://doi.org/10.1016/j.bbalip.2006.05.015
31. Klis, F.M.; Sosinska, G.J.; de Groot, P.W.J.; Brul, S. Covalently linked cell wall proteins of Candida albicans and their role in fitness and virulence. FEMS Yeast Res. 2009, 9, 1013–1028. DOI: https://doi.org/10.1111/j.1567-1364.2009.00541.x
32. Miyazaki, M.; Horii, T.; Hata, K.; Watanabe, N.-A.; Nakamoto, K.; Tanaka, K.; Shirotori, S.; Murai, N.; Inoue, S.; Matsukura, M.; et al. In vitro activity of E1210, a novel antifungal, against clinically important yeasts and molds. Antimicrob. Agents Chemother. 2011, 55, 4652–4658. DOI: https://doi.org/10.1128/AAC.00291-11
33. Oliver, J.D.; Sibley, G.E.M.; Beckmann, N.; Dobb, K.S.; Slater, M.J.; McEntee, L.; du Pré, S.; Livermore, J.; Bromley, M.J.; Wiederhold, N.P.; et al. F901318 represents a novel class of antifungal drug that inhibits dihydroorotate dehydrogenase. Proc. Natl. Acad. Sci. USA 2016, 113, 12809–12814. DOI: https://doi.org/10.1073/pnas.1608304113
34. Wiederhold, N.P. Review of the novel investigational antifungal olorofim. J. Fungi 2020, 6, 122. DOI: https://doi.org/10.3390/jof6030122
35. Pfaller, M.A.; Huband, M.D.; Flamm, R.K.; Bien, P.A.; Castanheira, M. Antimicrobial activity of manogepix, a first-in-class antifungal, and comparator agents tested against contemporary invasive fungal isolates from an international surveillance programme (2018–2019). J. Glob. Antimicrob. Resist. 2021, 26, 117–127. DOI: https://doi.org/10.1016/j.jgar.2021.04.012
36. Carrillo-Muñoz AJ, Giusiano G, Ezkurra PA, Quindós G. Antifungal agents: mode of action in yeast cells. Rev Esp Quimioter. 2006 Jun 1;19(2):130-9.
37. Jimenez-Garcia SN, Vazquez-Cruz MA, Guevara-Gonzalez RG, Torres-Pacheco I, Cruz-Hernandez A, Feregrino-Perez AA. Current approaches for enhanced expression of secondary metabolites as bioactive compounds in plants for agronomic and human health purposes-A review. Polish Journal of Food and Nutrition Sciences. 2013;63(2). DOI: https://doi.org/10.2478/v10222-012-0072-6
38. Huang W, Wang Y, Tian W, Cui X, Tu P, Li J, Shi S, Liu X. Biosynthesis Investigations of Terpenoid, Alkaloid, and Flavonoid Antimicrobial Agents Derived from Medicinal Plants. Antibiotics (Basel). 2022 Oct 9;11(10):1380. doi: 10.3390/antibiotics11101380. DOI: https://doi.org/10.3390/antibiotics11101380
39. Twaij BM, Hasan MN. Bioactive Secondary Metabolites from Plant Sources: Types, Synthesis, and Their Therapeutic Uses. International Journal of Plant Biology. 2022; 13(1):4-14. https://doi.org/10.3390/ijpb13010003 DOI: https://doi.org/10.3390/ijpb13010003
40. Elgharbawy A, Samsudin N, Hashim Y, Salleh H, Santhanam J. Ben belgacem, F. Phytochemicals with antifungal properties: Cure from nature. Int. J. Eng. Computat. 2020;16:323-45. DOI: http://dx.doi.org/10.21161/mjm. DOI: https://doi.org/10.21161/mjm.190551
41. Reshi ZA, Ahmad W, Lukatkin AS, Javed SB. From Nature to Lab: A Review of Secondary Metabolite Biosynthetic Pathways, Environmental Influences, and In Vitro Approaches. Metabolites. 2023 Jul 28;13(8):895. doi: 10.3390/metabo13080895. DOI: https://doi.org/10.3390/metabo13080895
42. Revutska A, Belava V, Golubenko A, Taran N, Chen M. Plant secondary metabolites as bioactive substances for innovative biotechnologies. InE3S Web of Conferences 2021 (Vol. 280, p. 07014). EDP Sciences. DOI: https://doi.org/10.1051/e3sconf/202128007014
43. Taff HT, Mitchell KF, Edward JA, Andes DR. Mechanisms of Candida biofilm drug resistance. Future Microbiol. 2013 Oct;8(10):1325-37. doi: 10.2217/fmb.13.101. DOI: https://doi.org/10.2217/fmb.13.101
44. Kovács R, Majoros L. Fungal quorum-sensing molecules: a review of their antifungal effect against Candida biofilms. Journal of Fungi. 2020 Jul 2;6(3):99. DOI: https://doi.org/10.3390/jof6030099
45. Stuckey PV, Santiago-Tirado FH. Fungal mechanisms of intracellular survival: what can we learn from bacterial pathogens?. Infection and Immunity. 2023 Sep 14;91(9):e00434-22. DOI: https://doi.org/10.1128/iai.00434-22
46. Dai X, Liu X, Li J, Chen H, Yan C, Li Y, Liu H, Deng D, Wang X. Structural insights into the inhibition mechanism of fungal GWT1 by manogepix. Nature Communications. 2024 Oct 24;15(1):9194. DOI: https://doi.org/10.1038/s41467-024-53512-x
47. Efremenko E, Aslanli A, Stepanov N, Senko O, Maslova O. Various Biomimetics, Including Peptides as Antifungals. Biomimetics. 2023 Oct 28;8(7):513. DOI: https://doi.org/10.3390/biomimetics8070513
48. Zhou X, Zeng M, Huang F, Qin G, Song Z, Liu F. The potential role of plant secondary metabolites on antifungal and immunomodulatory effect. Applied Microbiology and Biotechnology. 2023 Jun 5:1-22.
49. Cassidy A, Minihane AM. The role of metabolism (and the microbiome) in defining the clinical efficacy of dietary flavonoids. Am. J. Clin. Nutr. 2016;105:10–22. doi: 10.3945/ajcn.116.136051. DOI: https://doi.org/10.3945/ajcn.116.136051
50. Oteiza P.I., Fraga C.G., Mills D.A., Taft D.H. Flavonoids and the gastrointestinal tract: Local and systemic effects. Mol. Aspects Med. 2018;61:41–49. doi: 10.1016/j.mam.2018.01.001. DOI: https://doi.org/10.1016/j.mam.2018.01.001
51. El-Sakhawy MA. Combinational Effect of Selected Medicinal Plants and Antibiotics Against Pathogenic Bacteria. Pakistan Journal of Biological Sciences: PJBS. 2023 Feb 1;26(3):108-18. DOI: https://doi.org/10.3923/pjbs.2023.108.118
52. Rodríguez B, Pacheco L, Bernal I, Piña M. Mechanisms of Action of Flavonoids: Antioxidant, Antibacterial and Antifungal Properties. Ciencia, Ambiente y Clima. 2023 Dec 29;6(2):33-66. DOI: https://doi.org/10.22206/cac.2023.v6i2.3021
53. Ververidis F, Trantas E, Douglas C, Vollmer G, Kretzschmar G, Panopoulos N. Biotechnology of flavonoids and other phenylpropanoid‐derived natural products. Part I: Chemical diversity, impacts on plant biology and human health. Biotechnology Journal: Healthcare Nutrition Technology. 2007 Oct;2(10):1214-34. DOI: https://doi.org/10.1002/biot.200700084
54. Da X, Nishiyama Y, Tie D, Hein KZ, Yamamoto O, Morita E. Antifungal activity and mechanism of action of Ou-gon (Scutellaria root extract) components against pathogenic fungi. Scientific Reports. 2019 Feb 8;9(1):1683. doi:10.1038/s41598-019-38916-w. DOI: https://doi.org/10.1038/s41598-019-38916-w
55. Savu M, Ștefan M. anti-candida activity of flavonoids-an overview. Journal of Experimental & Molecular Biology. 2024 Jan 1;25(1). DOI: https://doi.org/10.47743/jemb-2024-126
56. Dai B-D, Cao Y-Y, Huang S, Xu Y-G, Gao P-H, Wang Y, Jiang Y-Y. 2009. Baicalein induces programmed cell death in Candida albicans. J Microbiol Biotechnol. 19(8):803–9. doi:10.4014/jmb.0812.662.
57. Kang K, Fong W-P, Tsang PW-K. 2010. Antifungal Activity of Baicalein Against Candida krusei Does Not Involve Apoptosis. Mycopathologia. 170(6):391–396. doi:10.1007/s11046-010-9341-2. DOI: https://doi.org/10.1007/s11046-010-9341-2
58. Cao Y, Dai B, Wang Y, Huang S, Xu Y, Cao Y, Gao P, Zhu Z, Jiang Y. In vitro activity of baicalein against Candida albicans biofilms. International journal of antimicrobial agents. 2008 Jul 1;32(1):73-7. DOI: https://doi.org/10.1016/j.ijantimicag.2008.01.026
59. Susilawati S, Anwar C, Saleh I, Salni S. Flavonoid as anti-Candida agents. IJFAC (Indonesian Journal of Fundamental and Applied Chemistry). 2023 Jun 27;8(2):88-97. DOI: https://doi.org/10.24845/ijfac.v8.i2.88
60. Navarro-Martínez MD, García-Cánovas F, RodríguezLópez JN. Tea polyphenol epigallocatechin-3-gallate inhibits ergosterol synthesis by disturbing folic acid metabolism in Candida albicans. J Antimicrob Chemother. 2006 Jun;57(6):1083–1092. DOI: https://doi.org/10.1093/jac/dkl124
61. Kong C, Zhang H, Li L, Liu Z. Effects of green tea extract epigallocatechin-3-gallate (EGCG) on oral disease-associated microbes: A review. Journal of Oral Microbiology. 2022 Dec 31;14(1):2131117. DOI: https://doi.org/10.1080/20002297.2022.2131117
62. Behbehani JM, Irshad M, Shreaz S, Karched M. Synergistic effects of tea polyphenol epigallocatechin 3-O-gallate and azole drugs against oral Candida isolates. J Mycol Med. 2019 Jun;29(2):158–167. DOI: https://doi.org/10.1016/j.mycmed.2019.01.011
63. Campos, F.M.; Couto, J.A.; Figueiredo, A.R.; To, I.V.; Rangel, A.O.S.; Hogg, T.A. Cell membrane damage induced by phenolic acids on wine lactic acid bacteria. Int. J. Food Microbiol. 2009, 135, 144–151. DOI: https://doi.org/10.1016/j.ijfoodmicro.2009.07.031
64. Thebti A, Meddeb A, Ben Salem I, Bakary C, Ayari S, Rezgui F, Essafi-Benkhadir K, Boudabous A, Ouzari HI. Antimicrobial activities and mode of flavonoid actions. Antibiotics. 2023 Jan 20;12(2):225. DOI: https://doi.org/10.3390/antibiotics12020225
65. Cushnie TT, Lamb AJ. Antimicrobial activity of flavonoids. International journal of antimicrobial agents. 2005 Nov 1;26(5):343-56. DOI: https://doi.org/10.1016/j.ijantimicag.2005.09.002
66. Havsteen BH. The biochemistry and medical significance of the flavonoids. Pharmacology & therapeutics. 2002 Nov 1;96(2-3):67-202. DOI: https://doi.org/10.1016/S0163-7258(02)00298-X
67. Middleton Jr E, Kandaswami C, Theoharides TC. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacological reviews. 2000 Dec 1;52(4):673-751. DOI: https://doi.org/10.1016/S0031-6997(24)01472-8
68. Mishra S, Pandey A, Manvati S. Coumarin: An emerging antiviral agent. Heliyon. 2020 Jan 1;6(1). DOI: https://doi.org/10.1016/j.heliyon.2020.e03217
69. Tsivileva OM, Koftin OV, Evseeva NV. Coumarins as fungal metabolites with potential medicinal properties. Antibiotics. 2022 Aug 26;11(9):1156. DOI: https://doi.org/10.3390/antibiotics11091156
70. Harbome, J. B.; Baxter, H. Phyochemical Dictionary. Taylor and Francis: London, 1993; pp. 351.
71. Sardari S, Nishibe S, Daneshtalab M. Coumarins, the bioactive structures with antifungal property. Studies in Natural Products Chemistry. 2000 Jan 1;23:335-93. DOI: https://doi.org/10.1016/S1572-5995(00)80133-7
72. Grigg GW. Genetic effects of coumarins. Mutation Research/Reviews in Genetic Toxicology. 1977 Jan 1;47(3-4):161-81. DOI: https://doi.org/10.1016/0165-1110(77)90002-1
73. Bordin F, Dall'acqua F, Guiotto A. Angelicins, angular analogs of psoralens: chemistry, photochemical, photobiological and phototherapeutic properties. Pharmacology & therapeutics. 1991 Dec 1;52(3):331-63. DOI: https://doi.org/10.1016/0163-7258(91)90031-G
74. Fowlks WL. Part IV: Basic Considerations of the Psoralens: The Mechanism of the Photodynamic Effect. Journal of Investigative Dermatology. 1959 Feb 1;32(2):233-47. DOI: https://doi.org/10.1038/jid.1959.41
75. Widodo GP, Sukandar EY, Adnyana IK, Sukrasno S. Mechanism of Action of Coumarin against Candida albicans by SEM/TEM Analysis. ITB J. Sci. 2012;44:145-51. DOI: https://doi.org/10.5614/itbj.sci.2012.44.2.4
76. Neto FC, Dietrich SM. Effect of coumarin on growth and metabolism of Pythium. Appl Environ Microbiol. 1977 Sep;34(3):258-62. doi: 10.1128/aem.34.3.258-262.1977. DOI: https://doi.org/10.1128/aem.34.3.258-262.1977
77. Kaiser E, Kramar R, Farkouh E. Imperatorin, a respiration inhibitor of succinate oxidation in liver mitochondria. Enzymologia. 1966 Jan 31;30(1):64-8.
78. Knypl JS (1968): Coumarin and indole-3-acetic acid induced growth and respiration in sun-flower as affected by 2- chloroethyl-3-methylammonium chloride, actinomycin C, puromycin and diazouracil. Acta Soc Bot Pol 37: 51–60 DOI: https://doi.org/10.5586/asbp.1968.006
79. Kupidlowska E, Dobrzynska K, Parys E, Zobel AM. Effect of coumarin and xanthotoxin on mitochondrial structure, oxygen uptake, and succinate dehydrogenase activity in onion root cells. Journal of chemical ecology. 1994 Oct;20:2471-80. DOI: https://doi.org/10.1007/BF02036184
80. Şeker Karatoprak G, Dumlupınar B, Celep E, Kurt Celep I, Küpeli Akkol E, Sobarzo-Sánchez E. A comprehensive review on the potential of coumarin and related derivatives as multi-target therapeutic agents in the management of gynecological cancers. Front Pharmacol. 2024 Sep 16;15:1423480. doi: 10.3389/fphar.2024.1423480. DOI: https://doi.org/10.3389/fphar.2024.1423480
81. Chuang JY, Huang YF, Lu HF, Ho HC, Yang JS, Li TM, Chang NW, Chung JG. Coumarin induces cell cycle arrest and apoptosis in human cervical cancer HeLa cells through a mitochondria-and caspase-3 dependent mechanism and NF-κB down-regulation. In vivo. 2007 Nov 1;21(6):1003-9.
82. Mercer DK, Robertson J, Wright K, Miller L, Smith S, Stewart CS, O′ Neil DA. A prodrug approach to the use of coumarins as potential therapeutics for superficial mycoses. PLoS One. 2013 Nov 18;8(11):e80760. DOI: https://doi.org/10.1371/journal.pone.0080760
83. Garro HA, Pungitore CR. Coumarins as Potential Inhibitors of DNA Polymerases and Reverse Transcriptases. Searching New Antiretroviral and Antitumoral Drugs. Curr Drug Discov Technol. 2015;12(2):66-79. doi:10.2174/1570163812666150716111719. DOI: https://doi.org/10.2174/1570163812666150716111719
84. Alt S, Mitchenall LA, Maxwell A, Heide L. Inhibition of DNA gyrase and DNA topoisomerase IV of Staphylococcus aureus and Escherichia coli by aminocoumarin antibiotics. Journal of antimicrobial chemotherapy. 2011 Sep 1;66(9):2061-9. DOI: https://doi.org/10.1093/jac/dkr247
85. Borges F, Roleira F, Milhazes N, Santana L, Uriarte E. Simple coumarins and analogues in medicinal chemistry: occurrence, synthesis and biological activity. Curr Med Chem. 2005;12(8):887-916. doi: 10.2174/0929867053507315. DOI: https://doi.org/10.2174/0929867053507315
86. Stefanachi A, Leonetti F, Pisani L, Catto M, Carotti A. Coumarin: A natural, privileged and versatile scaffold for bioactive compounds. Molecules. 2018 Jan 27;23(2):250. DOI: https://doi.org/10.3390/molecules23020250
87. Jia C, Zhang J, Yu L, Wang C, Yang Y, Rong X, Xu K, Chu M. Antifungal activity of coumarin against Candida albicans is related to apoptosis. Frontiers in Cellular and Infection Microbiology. 2019 Jan 4;8:445. DOI: https://doi.org/10.3389/fcimb.2018.00445
88. Huang J, Zaynab M, Sharif Y, Khan J, Al-Yahyai R, Sadder M, Ali M, Alarab SR, Li S. Tannins as antimicrobial agents: Understanding toxic effects on pathogens. Toxicon. 2024 Aug 28;247:107812. doi: 10.1016/j.toxicon.2024.107812. DOI: https://doi.org/10.1016/j.toxicon.2024.107812
89. Zhu C, Lei M, Andargie M, Zeng J, Li J. Antifungal activity and mechanism of action of tannic acid against Penicillium digitatum. Physiological and Molecular Plant Pathology. 2019 Aug 1;107:46-50. DOI: https://doi.org/10.1016/j.pmpp.2019.04.009
90. Moreira LEA, de Farias Cabral VP, Rodrigues DS, Barbosa AD, Silveira MJCB, Coutinho TDNP, Barbosa SA, Sá LGDAV, de Andrade Neto JB, da Rocha SNC, Reis CS, Cavalcanti BC, Rios MEF, de Moraes MO, Júnior HVN, da Silva CR. Antifungal activity of tannic acid against Candida spp. and its mechanism of action. Braz J Microbiol. 2024 Dec;55(4):3679-3690. doi: 10.1007/s42770-024-01477-w. DOI: https://doi.org/10.1007/s42770-024-01477-w
91. Villanueva X, Zhen L, Ares JN, Vackier T, Lange H, Crestini C, Steenackers HP. Effect of chemical modifications of tannins on their antimicrobial and antibiofilm effect against Gram-negative and Gram-positive bacteria. Frontiers in Microbiology. 2023 Jan 6;13:987164. DOI: https://doi.org/10.3389/fmicb.2022.987164
92. Abe, I.; Kashiwagi, Y.; Noguchi, H.; Tanaka, T.; Ikeshiro, Y.; Kashiwada, Y. Ellagitannins and Hexahydroxydiphenoyl Esters as Inhibitors of Vertebrate Squalene Epoxidase. J. Nat. Prod. 2001, 64, 1010–1014. DOI: https://doi.org/10.1021/np010100y
93. Brighenti V, Iseppi R, Pinzi L, Mincuzzi A, Ippolito A, Messi P, Sanzani SM, Rastelli G, Pellati F. Antifungal activity and DNA topoisomerase inhibition of hydrolysable tannins from Punica granatum L. International Journal of Molecular Sciences. 2021 Apr 17;22(8):4175. DOI: https://doi.org/10.3390/ijms22084175
94. Scalbert A. Antimicrobial properties of tannins. Phytochemistry. 1991 Jan 1;30(12):3875-83. DOI: https://doi.org/10.1016/0031-9422(91)83426-L
95. Haslam E. Natural polyphenols (vegetable tannins) as drugs: possible modes of action. Journal of natural products. 1996 Feb 22;59(2):205-15. DOI: https://doi.org/10.1021/np960040+
96. Chung KT, Wong TY, Wei CI, Huang YW, Lin Y. Tannins and human health: a review. Critical reviews in food science and nutrition. 1998 Aug 1;38(6):421-64. DOI: https://doi.org/10.1080/10408699891274273
97. Yang Y, Zhang T. Antimicrobial activities of tea polyphenol on phytopathogens: A review. Molecules. 2019 Feb 25;24(4):816. DOI: https://doi.org/10.3390/molecules24040816
98. Sanzani SM, Schena L, De Girolamo A, Ippolito A, González-Candelas L. Characterization of genes associated with induced resistance against Penicillium expansum in apple fruit treated with quercetin. Postharvest biology and technology. 2010 Apr 1;56(1):1-1. DOI: https://doi.org/10.1016/j.postharvbio.2009.11.010
99. Mishra AP, Swetanshu, Singh P, Yadav S, Nigam M, Seidel V, Rodrigues CF. Role of the Dietary Phytochemical Curcumin in Targeting Cancer Cell Signalling Pathways. Plants (Basel). 2023 Apr 26;12(9):1782. doi: 10.3390/plants12091782. DOI: https://doi.org/10.3390/plants12091782
100. Rege SA, Arya M, Momin SA. Structure activity relationship of tautomers of curcumin: A review. Ukrainian food journal. 2019(8, Issue 1):45-60. DOI: https://doi.org/10.24263/2304-974X-2019-8-1-6
101. Lee W, Lee DG. An antifungal mechanism of curcumin lies in membrane‐targeted action within C andida albicans. IUBMB life. 2014 Nov;66(11):780-5. DOI: https://doi.org/10.1002/iub.1326
102. Andrade JT, de Figueiredo GF, Cruz LF, de Morais SE, Souza CD, Pinto FC, Ferreira JM, de Freitas Araújo MG. Efficacy of curcumin in the treatment of experimental vulvovaginal candidiasis. Revista Iberoamericana De Micologia. 2019 Oct 1;36(4):192-9. DOI: https://doi.org/10.1016/j.riam.2019.01.003
103. Fang X, Wu H, Wei J, Miao R, Zhang Y, Tian J. Research progress on the pharmacological effects of berberine targeting mitochondria. Front Endocrinol (Lausanne). 2022 Aug 11;13:982145. doi: 10.3389/fendo.2022.982145. DOI: https://doi.org/10.3389/fendo.2022.982145
104. Ciorîță A, Erhan SE, Soran ML, Lung I, Mot AC, Macavei SG, Pârvu M. Pharmacological Potential of Three Berberine-Containing Plant Extracts Obtained from Berberis vulgaris L., Mahonia aquifolium (Pursh) Nutt., and Phellodendron amurense Rupr. Biomedicines. 2024 Jun 17;12(6):1339. DOI: https://doi.org/10.3390/biomedicines12061339
105. Shahina Z, Dahms TE. A comparative review of eugenol and citral anticandidal mechanisms: Partners in crimes against fungi. Molecules. 2024 Nov 23;29(23):5536. DOI: https://doi.org/10.3390/molecules29235536
106. Chen C, Long LI, Zhang F, Chen Q, Chen C, Yu X, Liu Q, Bao J, Long Z. Antifungal activity, main active components and mechanism of Curcuma longa extract against Fusarium graminearum. PloS one. 2018 Mar 15;13(3):e0194284.https://doi.org/10.1371/journal. pone.0194284 DOI: https://doi.org/10.1371/journal.pone.0194284
107. Martins CV, Da Silva DL, Neres AT, Magalhaes TF, Watanabe GA, Modolo LV, Sabino AA, De Fátima A, De Resende MA. Curcumin as a promising antifungal of clinical interest. Journal of Antimicrobial Chemotherapy. 2009 Feb 1;63(2):337-9. DOI: https://doi.org/10.1093/jac/dkn488
108. Tyagi P, Singh M, Kumari H, Kumari A, Mukhopadhyay K. Bactericidal activity of curcumin I is associated with damaging of bacterial membrane. PloS one. 2015 Mar 26;10(3):e0121313. DOI: https://doi.org/10.1371/journal.pone.0121313
109. Sharma M, Manoharlal R, Puri N, Prasad R. Antifungal curcumin induces reactive oxygen species and triggers an early apoptosis but prevents hyphae development by targeting the global repressor TUP1 in Candida albicans. Bioscience reports. 2010 Dec 1;30(6):391-404. DOI: https://doi.org/10.1042/BSR20090151
110. Al-Khayri JM, Rashmi R, Toppo V, Chole PB, Banadka A, Sudheer WN, Nagella P, Shehata WF, Al-Mssallem MQ, Alessa FM, Almaghasla MI, Rezk AA. Plant Secondary Metabolites: The Weapons for Biotic Stress Management. Metabolites. 2023 May 31;13(6):716. doi: 10.3390/metabo13060716. DOI: https://doi.org/10.3390/metabo13060716
111. Huang T, Jander G, de Vos M. Non-protein amino acids in plant defense against insect herbivores: representative cases and opportunities for further functional analysis. Phytochemistry. 2011 Sep;72(13):1531-7. doi: 10.1016/j.phytochem.2011.03.019. DOI: https://doi.org/10.1016/j.phytochem.2011.03.019
112. Heinrich M, Mah J, Amirkia V. Alkaloids Used as Medicines: Structural Phytochemistry Meets Biodiversity-An Update and Forward Look. Molecules. 2021 Mar 25;26(7):1836. doi: 10.3390/molecules26071836. DOI: https://doi.org/10.3390/molecules26071836
113. Dey P, Kundu A, Kumar A, Gupta M, Lee BM, Bhakta T, Dash S, Kim HS. Analysis of alkaloids (indole alkaloids, isoquinoline alkaloids, tropane alkaloids). Recent Advances in Natural Products Analysis. 2020:505–67. doi: 10.1016/B978-0-12-816455-6.00015-9. DOI: https://doi.org/10.1016/B978-0-12-816455-6.00015-9
114. Aryal B, Raut BK, Bhattarai S, Bhandari S, Tandan P, Gyawali K, Sharma K, Ranabhat D, Thapa R, Aryal D, Ojha A, Devkota HP, Parajuli N. Potential Therapeutic Applications of Plant-Derived Alkaloids against Inflammatory and Neurodegenerative Diseases. Evid Based Complement Alternat Med. 2022 Mar 9;2022:7299778. doi: 10.1155/2022/7299778. DOI: https://doi.org/10.1155/2022/7299778
115. Vishwakarma M, Haider T, Soni V. Update on fungal lipid biosynthesis inhibitors as antifungal agents. Microbiological Research. 2024 Jan 1;278:127517. DOI: https://doi.org/10.1016/j.micres.2023.127517
116. Quan H, Cao YY, Xu Z, Zhao JX, Gao PH, Qin XF, Jiang YY. Potent in vitro synergism of fluconazole and berberine chloride against clinical isolates of Candida albicans resistant to fluconazole. Antimicrobial Agents and Chemotherapy. 2006 Mar;50(3):1096-9. DOI: https://doi.org/10.1128/AAC.50.3.1096-1099.2006
117. Xu Y, Wang Y, Yan L, Liang RM, Dai BD, Tang RJ, Gao PH, Jiang YY. Proteomic analysis reveals a synergistic mechanism of fluconazole and berberine against fluconazole-resistant Candida albicans: endogenous ROS augmentation. Journal of Proteome Research. 2009 Nov 6;8(11):5296-304. DOI: https://doi.org/10.1021/pr9005074
118. Purwaningsih I, Maksum IP, Sumiarsa D, Sriwidodo S. A review of Fibraurea tinctoria and its component, berberine, as an antidiabetic and antioxidant. Molecules. 2023 Jan 29;28(3):1294. DOI: https://doi.org/10.3390/molecules28031294
119. da Silva AR, de Andrade Neto JB, da Silva CR, Campos RD, Costa Silva RA, Freitas DD, do Nascimento FB, de Andrade LN, Sampaio LS, Grangeiro TB, Magalhães HI. Berberine antifungal activity in fluconazole-resistant pathogenic yeasts: action mechanism evaluated by flow cytometry and biofilm growth inhibition in Candida spp. Antimicrobial agents and chemotherapy. 2016 Jun;60(6):3551-7. DOI: https://doi.org/10.1128/AAC.01846-15
120. Xie Y, Liu X, Zhou P. In vitro antifungal effects of berberine against Candida spp. in planktonic and biofilm conditions. Drug design, development and therapy. 2020 Jan 9:87-101. DOI: https://doi.org/10.2147/DDDT.S230857
121. Alyousef AA. Antifungal Activity and Mechanism of Action of Different Parts of Myrtus communis Growing in Saudi Arabia against Candida Spp. Journal of Nanomaterials. 2021 Oct 7;2021:1-0. https://doi.org/10.1155/2021/3484125 DOI: https://doi.org/10.1155/2021/3484125
122. Kamal LZ, Adam MA, Shahpudin SN, Shuib AN, Sandai R, Hassan NM, Tabana Y, Basri DF, Than LT, Sandai D. Identification of alkaloid compounds Arborinine and Graveoline from Ruta angustifolia (L.) Pers for their antifungal potential against Isocitrate lyase (ICL 1) gene of Candida albicans. Mycopathologia. 2021 May;186:221-36.https:// doi. org/ 10. 1007/s11046- 020- 00523-z DOI: https://doi.org/10.1007/s11046-020-00523-z
123. Kim J, Ha Quang Bao T, Shin YK, Kim KY. Antifungal activity of magnoflorine against Candida strains. World Journal of Microbiology and Biotechnology. 2018 Nov;34:1-7.https:// doi. org/ 10. 1007/ s11274- 018- 2549-x DOI: https://doi.org/10.1007/s11274-018-2549-x
124. Luo N, Jin L, Yang C, Zhu Y, Ye X, Li X, Zhang B. Antifungal activity and potential mechanism of magnoflorine against Trichophyton rubrum. The Journal of Antibiotics. 2021 Mar;74(3):206-14. DOI: https://doi.org/10.1038/s41429-020-00380-4
125. Huang X, Yi Y, Yong J, Sun J, Song Z, Li D, Li Y. Inhibitory effect of berberine hydrochloride against Candida albicans and the role of the HOG-MAPK pathway. The Journal of Antibiotics. 2021 Nov;74(11):807-16.https:// doi. org/ 10. 1038/ s41429- 021- 00463-w DOI: https://doi.org/10.1038/s41429-021-00463-w
126. Cushnie TT, Cushnie B, Lamb AJ. Alkaloids: An overview of their antibacterial, antibiotic-enhancing and antivirulence activities. International journal of antimicrobial agents. 2014 Nov 1;44(5):377-86. DOI: https://doi.org/10.1016/j.ijantimicag.2014.06.001
127. Evidente A, Kornienko A, Cimmino A, Andolfi A, Lefranc F, Mathieu V, Kiss R. Fungal metabolites with anticancer activity. Natural product reports. 2014;31(5):617-27. DOI: https://doi.org/10.1039/C3NP70078J
128. Molyneux RJ, McKenzie RA, O'Sullivan BM, Elbein AD. Identification of the glycosidase inhibitors swainsonine and calystegine B2 in weir vine (Ipomoea sp. Q6 {aff. calobra}) and correlation with toxicity. Journal of Natural Products. 1995 Jun;58(6):878-86. DOI: https://doi.org/10.1021/np50120a009
129. Bian GK, Ma T, Liu TG. Chapter Five-in vivo platforms for terpenoid overproduction and the generation of chemical diversity. Methods in enzymology. https://doi. org/10.1016/bs. mie. 2018;25. DOI: https://doi.org/10.1016/bs.mie.2018.04.025
130. Konuk HB, Ergüden B. Phenolic -OH group is crucial for the antifungal activity of terpenoids via disruption of cell membrane integrity. Folia Microbiol (Praha). 2020 Aug;65(4):775-783. doi: 10.1007/s12223-020-00787-4. DOI: https://doi.org/10.1007/s12223-020-00787-4
131. Rao A, Zhang Y, Muend S, Rao R. Mechanism of antifungal activity of terpenoid phenols resembles calcium stress and inhibition of the TOR pathway. Antimicrob Agents Chemother. 2010 Dec;54(12):5062-9. doi: 10.1128/AAC.01050-10. DOI: https://doi.org/10.1128/AAC.01050-10
132. El-Sakhawy MA, Soliman GA, El-Sheikh HH, Ganaie MA. Anticandidal effect of Eucalyptus oil and three isolated compounds on cutaneous wound healing in rats. European Review for Medical & Pharmacological Sciences. 2023 Jan 1;27(1).
133. Raj N, Parveen, Khatoon S, Manzoor N. Antifungal Efficacy of Terpenes and Mechanism of Action Against Human Pathogenic Fungi. InAdvances in Antifungal Drug Development: Natural Products with Antifungal Potential 2024 Aug 30 (pp. 315-341). Singapore: Springer Nature Singapore.https://doi.org/10.1007/978-981-97-5165-5_11 DOI: https://doi.org/10.1007/978-981-97-5165-5_11
134. Wiart C, Kathirvalu G, Raju CS, Nissapatorn V, Rahmatullah M, Paul AK, Rajagopal M, Sathiya Seelan JS, Rusdi NA, Lanting S, Sulaiman M. Antibacterial and Antifungal Terpenes from the Medicinal Angiosperms of Asia and the Pacific: Haystacks and Gold Needles. Molecules. 2023 May 4;28(9):3873. doi: 10.3390/molecules28093873. DOI: https://doi.org/10.3390/molecules28093873
135. Nazzaro, F., Fratianni, F., De Martino, L., Coppola, R., & De Feo, V. (2013). Effect of essential oils on pathogenic bacteria. Pharmaceuticals, 6(12), 1451-1474. DOI: https://doi.org/10.3390/ph6121451
136. Raut JS, Karuppayil SM. A status review on the medicinal properties of essential oils. Industrial crops and products. 2014 Dec 1;62:250-64. DOI: https://doi.org/10.1016/j.indcrop.2014.05.055
137. Bakkali F, Averbeck S, Averbeck D, Idaomar M. Biological effects of essential oils–a review. Food and chemical toxicology. 2008 Feb 1;46(2):446-75. DOI: https://doi.org/10.1016/j.fct.2007.09.106
138. Vincken JP, Heng L, de Groot A, Gruppen H. Saponins, classification and occurrence in the plant kingdom. Phytochemistry. 2007 Feb 1;68(3):275-97. DOI: https://doi.org/10.1016/j.phytochem.2006.10.008
139. Faizal A, Geelen D. Saponins and their role in biological processes in plants. Phytochemistry reviews. 2013 Dec; 12:877-93. DOI: https://doi.org/10.1007/s11101-013-9322-4
140. Osbourn A. Saponins and plant defence—a soap story. Trends in plant science. 1996 Jan 1;1(1):4-9. DOI: https://doi.org/10.1016/S1360-1385(96)80016-1
141. Kregiel D, Berlowska J, Witonska I, Antolak H, Proestos C, Babic M, Babic L, Zhang B. Saponin-based, biological-active surfactants from plants. InApplication and characterization of surfactants 2017 Jul 5. intechopen. DOI: https://doi.org/10.5772/68062
142. Saniewska A, Jarecka A, Bialy Z, Jurzysta M. Antifungal activity of saponins originated from Medicago hybrida against some ornamental plant pathogens. Acta Agrobotanica. 2006;59(2). DOI: https://doi.org/10.5586/aa.2006.061
143. Bonanomi G, Vinale F, Scala F. The role of natural products in plant-microbe interactions. Plant-derived Natural Products: Synthesis, Function, and Application. 2009:301-20. DOI: https://doi.org/10.1007/978-0-387-85498-4_14
144. Morant AV, Jorgensen K, Jorgensen C, Paquette SM, Sanchez- Perez R, Moller BL, Bak S (2008) beta-glucosidases as detonators of plant chemical defense. Phytochemistry 69:1795–1813 DOI: https://doi.org/10.1016/j.phytochem.2008.03.006
145. Augustin JM, Kuzina V, Andersen SB, Bak S. Molecular activities, biosynthesis and evolution of triterpenoid saponins. Phytochemistry. 2011 Apr 1;72(6):435-57. DOI: https://doi.org/10.1016/j.phytochem.2011.01.015
146. Wei M, Chen Q, Zhou Y, Tie H. The influence of synergistic antibacterial saponins, sapindoside A and B, on the fatty acid composition and membrane properties of Micrococcus luteus. Journal of the Science of Food and Agriculture. doi: 10.1002/jsfa.1405. DOI: https://doi.org/10.1002/jsfa.1405
147. Zong JF, Hong ZB, Hu ZH, Hou RY. Two New Triterpenoid Saponins with Antifungal Activity from Camellia sinensis Flowers. International Journal of Molecular Sciences. 2025 Jan 28;26(3):1147.https://doi.org/10.3390/ijms26031147 DOI: https://doi.org/10.3390/ijms26031147
148. Sparg SG, Light ME, van Staden J. Biological activities and distribution of plant saponins. J Ethnopharmacol. 2004;94:219–243. DOI: https://doi.org/10.1016/j.jep.2004.05.016
149. Lemeshko VV, Haridas V, Quijano Pérez JC, Gutterman JU. Avicins, natural anticancer saponins, permeabilize mitochondrial membranes. Arch Biochem Biophys. 2006;454:114–122. DOI: https://doi.org/10.1016/j.abb.2006.08.008
150. Ouyang M, Wu J, Hu X, Liu C, Zhou D. Decoding the power of saponins in ferroptosis regulation and disease intervention: a review. Journal of Pharmacy and Pharmacology. 2024 Nov 30:rgae144.https://doi.org/10.1093/jpp/rgae144 DOI: https://doi.org/10.1093/jpp/rgae144
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