Unraveling the importance of molecules of natural origin in antifungal drug development through targeting ergosterol biosynthesis pathway
Over the past decades, the incidence of life-threatening fungal infections has increased dramatically in particular among patients with hampered immune function. Fungal infections cause around 1.5 million deaths annually, superior to malaria and tuberculosis. With respect to high toxicity, narrow spectrum of activity and drug resistance to current antifungals, there is an urgent need to discover novel leads from molecules of natural origin especially those derived from plants and microorganisms for antifungal drug discovery. Among antifungal drugs introduced into the clinic, those affecting ergosterol biosynthesis are still superior to other classes and the vital role of ergosterol in fungal growth and development. This review highlights current knowledge about available antifungal agents and further issues on antifungal drug discovery from compounds of natural origin which affect ergosterol biosynthesis. Special attention is made to the fungal sterol C24-methyltransferase (SMT), a crucial enzyme in ergosterol biosynthesis pathway as a novel target for rational drug design.
2. Calderone R, Sun N, Gay-Andrieu F, Groutas W, Weerawarna P, Prasad S, et al. Antifungal drug discovery: the process and outcomes. Future Microbiol 2014; 9: 791-805.
3. Ostrosky-Zeichner L, Casadevall A, Galgiani JN , Odds FC, Rex JH. An insight into the antifungal pipeline: selected new molecules and beyond. Nat Rev Drug Discov 2010; 9: 719-727.
4. Roemer T, Xu DB, Singh SB, Parish CA, Harris G, Wang H, et al. Confronting the challenges of natural product-based antifungal discovery. Chem Biol 2011; 18: 148-164.
5. Razzaghi-Abyaneh M, Shams-Ghahfarokhi M, Rai M. Antifungal Metabolites from Plants. First Edition, Springer-Verlag, Germany, 2013.
6. Jahanshiri Z, Shams-Ghahfarokhi M, Asghari-Paskiabi F, Saghiri R, Razzaghi-Abyaneh M. α-Bisabolol inhibits Aspergillus fumigatus Af239 growth via affecting microsomal ∆24-sterol methyltransferase as a crucial enzyme in ergosterol biosynthesis pathway. World J Microbiol Biotechnol 2017; 33: 55.
7. Abad MJ, Ansuategui M, Bermejo P. Active antifungal substances from natural sources. ARKIVOC 2007; 8: 116-145.
8. Rex JH, Walsh TJ, Nettleman M, Anaissie EJ, Bennett JE, Bow EJ, et al. Need for alternative trial designs and evaluation strategies for therapeutic studies of invasive mycoses. Clin Infect Dis 2001; 33: 95-106.
9. Boucher HW, Talbot GH, Bradley JS, Edwards JE, Gilbert D, Rice LB, et al. Bad bugs, no drugs: no ESKAPE! An update from the infectious diseases society of America. Clin Infect Dis 2009; 48:1-12.
10. Roemer T, Krysan D. Antifungal Drug Development: Challenges, Unmet Clinical Needs, and New Approaches. Cold Spring Harbor Laboratory Press, 2017.
11. Peláez F, Cabello A, Platas G, Díez MT, Gonzálezdelval A, Basilio A, et al. The discovery of enfumafungin, a novel antifungal compound produced by an endophytic Hormonema species biological activity and taxonomy of the producing organisms. Syst Appl Microbiol 2000; 23: 333-343.
12. Krysan DJ, Didone L. A high-throughput screening assay for small molecules that disrupt yeast cell integrity. J Biomol Screen 2008; 13: 657-664.
13. Tebbets B, Stewart D, Lawry S, Nett J, Nantel A, Andes D, et al. Identification and characterization of antifungal compounds using a Saccharomyces cerevisiae reporter bioassay. PLoS One 2012; 7(5):e36021.
14. Di Santo R. Natural products as antifungal agents against clinically relevant pathogens. Nat Prod Rep 2010; 27: 1084-1098.
15. Jahanshiri Z, Shams-Ghahfarokhi M, Allameh A, Razzaghi-Abyaneh M. Inhibitory effect of eugenol on aflatoxin B1 production in Aspergillus parasiticus by downregulating the expression of major genes in the toxin biosynthetic pathway. World J Microbiol Biotechnol 2015; 31: 1071-1078.
16. Hopkin A, Groom C. The druggable genome. Nat Rev Drug Discov 2002; 1: 727-730.
17. Zhang L, Chang JJ, Zhang SL, Damu GLV, Geng R-X, Zhou C-H. Synthesis and bioactive evaluation of novel hybrids of metronidazole and berberine as new types of antimicrobial agents and their transportation behavior by human serum albumin. Bioorg Med Chem 2013; 21: 4158-4169.
18. Li D, Xu Y, Zhang D-Z, Quan H, Mylonakis E, Hu, D-D, et al. Fluconazole assists berberine to kill fluconazole-resistant Candida albicans. Antimicrob Agents Chemother 2013; 57: 6016-6027.
19. Sima Sadat Seyedjavadi, Soghra Khani, Hadi Zare-Zardini, Raheleh Halabian, Mehdi Goudarzi, Shohreh Khatami, et al. Isolation, functional characterization biological properties of MCh-AMP1,a novel antifungal peptide from Matricaria chamomilla L. Chem Biol Drug Des 2019; 93: 949-959.
20. Soghra Khani, Sima Sadat Seyedjavadi, Hadi Zare-Zardini, Hamideh Mahmoodzadeh Hosseini, Mehdi Goudarzi, Shohreh Khatami, et al. Isolation and functional characterization of an antifungal hydrophilic peptide, Skh-AMP1, derived from Satureja khuzistanica leaves. Phytochemistry 2019;164: 136-143.
21. Gunther R, Carle R, Fleishhauer CI, Merget S. Semi-preparative liquid-chromatographic separation of all four stereoisomers of α-bisabolol on tribenzoylcellulose. "Fresenius J Anal Chem 1993; 345: 787-790.
22. Razzaghi-Abyaneh M, Shams-Ghahfarokhi M, Rai M. (2013) Antifungal Plants of Iran: An Insight into Ecology, Chemistry, and Molecular Biology. In: Antifungal Metabolites from Plants. Ed, M. Razzaghi-Abyaneh, M. Rai. Springer-Verlag Berlin Heidelberg, pp. 27-57.
23. Liu J, Nes WD. Steroidal Triterpenes: Design of substrate-based Inhibitors of ergosterol and sitosterol synthesis. Molecules 2009; 14: 4690-4706.
24. Tolouee M, Alinezhad S, Saberi R, Eslamifar A, Zad SJ, Jaimand K, et al. Effect of Matricaria chamomilla L. flower essential oil on the growth and ultrastructure of Aspergillus niger van Tieghem. Int J Food Microbiol 2010; 139: 127-133.
25. Jamalian A, Shams-Ghahfarokhi M, Jaimand K, Pashootan N, Amani A, Razzaghi-Abyaneh M. Chemical composition and antifungal activity of Matricaria recutita flower essential oil against medically important dermatophytes and soil-borne pathogens. J Mycol Med 2012; 22: 308-315.
26. Isaac O, Thiemer K. [Biochemical studies on camomile components/III. In vitro studies about the antipeptic activity of (--)-alpha-bisabolol (author's transl)]. Arzneimittelforschung 1975; 25: 1352-1354.
27. Viljoen AM, Gono-Bwalya AB, Kamatou GPP, Baser KHC, Demirci B. The essential oil composition and chemotaxonomy of Salvia stenophylla and its allies S. repens and S. runcinata. J Essent Oil Res 2006; 18: 37-45.
28. De Souza AT, Benazzi TL, Grings MB, Cabral V, da Silva EA, Cardozo-Filho L, et al. Supercritical extraction process and phase equilibrium of Candeia (Eremanthus erythropappus) oil using supercritical carbon dioxide. J Supercrit Fluid 2008; 47: 182-187.
29. Williams AC, Barry BW. Terpenes and the lipid-proteinpartitioning theory of skin penetration enhancement. Pharm Res 1991; 8: 17-24.
30. Brehm-Stecher B, Johnson EA. Sensitization of Staphylococcus aureus and Escherichia coli by the sesquiterpenoids nerolidol, farnesol, bisabolol, and apritone. Antimicrob Agents Chemother 2003; 47: 3357-3360.
31. Van Zyl RL, Seatlholo ST, Van Vuuren SF, Viljoen AM. The biological activities of 20 nature identical essential oil constituents. J Essent Oil Res 2006; 18:129-133.
32. Cavalieri E, Bergamini C, Mariogotto S, Leoni S, Perbellini L, Darra E, et al. Involvement of mitochondrial permeability transition pore opening in α-bisabolol induced apoptosis. FEBS J 2009; 276: 3990-4000.
33. Pauli A. α-Bisabolol from Chamomile–A specific ergosterol biosynthesis inhibitor? Int J Aromather 2006; 16: 21-25.
34. Romagnoli C, Baldisserotto A, Malisardi G, Vicentini CB, Mares D, Andreotti E, et al. A multi-target approach toward the development of novel candidates for antidermatophytic activity: Ultrastructural evidence on α-bisabolol-Treated Microsporum gypseum. Molecules 2015; 20: 11765-11776.
35. Jahanshiri Z, Shams-Ghahfarokhi M, Allameh A, Razzaghi-Abyaneh M. Effect of curcumin on Aspergillus parasiticus growth and expression of major genes involved in the early and late stages of aflatoxin biosynthesis. Iran J Public Health 2012; 41: 72-79.
36. Pianaro A, Pereira Pinto J, Ferreira DT, Kazue Ishikawa N, Braz-Filho R. Iridoid glucoside and antifungal phenolic compounds from Spathodea campanulata roots. Semin Cienc Agrar 2007; 28:251-255.
37. Zhang L, Chang W, Sun B, Groh M, Speicher A, Lou H. Bisbibenzyls, a new type of antifungal agent, inhibit morphogenesis switch and biofilm formation through upregulation of DPP3 in Candida albicans. PLoS One 2011; 6(12):e28953.
38. Peeler TC, Stephenson NB, Einspahr KJ, Tompson GA. Lipid characterization of an enriched plasma membrane fraction of Dunaliella salina grown in media of varying salinity. Plant Physiol 1989; 89: 970-976.
39. Faria NCG, Kim JH, Goncalves LAP, Martins MDL, Chan KL, Campbell BC. Enhanced activity of antifungal drugs using natural phenolics against yeast strains of Candida and Cryptococcus. Lett Appl Microbiol 2011; 52: 506-513.
40. Kim J, Campbell B, Mahoney N, Chan K, Molyneux R, May G. Chemosensitization prevents tolerance of Aspergillus fumigatus to antimycotic drugs. Biochem Biophys Res Commun 2008; 372: 266-271.
41. Guo N, Liu J, Wu X, Bi X, Meng R, Wang X, et al. Antifungal activity of thymol against clinical isolates of fluconazole-sensitive and –resistant Candida albicans. J Med Microbiol 2009; 58: 1074-1079.
42. Shukla A, Dwivedi SK. Antifungal approach of phenolic compounds against Fusarium udum and Fusarium oxysporum f. sp. ciceri. Afr J Agric Res 2013; 8: 596-600.
43. Alex D, Gay-Andrieu F, May J, Thampi L, Dou D, Mooney A, et al. Amino acid derived 1,2-benzisothiazolinone derivatives as novel small molecule inhibitors: identification of potential genetic targets. Antimicrob Agents Chemother 2012; 56: 4630-4639.
44. Dou D, Alex D, Du B, Tiew KC, Aravapallis S, Mandadapu SR, et al. Antifungal activity of a series of 1,2-benzisothiazol- 3(2H)-one derivatives. Bioorg Med Chem 2011; 19: 5782-5787.
45. Hoepfner D, Karkaree S, Helliwell S, Pfeifer M, Trunzer M, De Bonnechose S, et al. An integrated approach for identification and target validation of antifungal compounds active against Erg11p. Antimicrob Agents Chemother 2012; 56: 4233-4240.
46. Barrett-Bee K, Dixon G. Ergosterol biosynthesis inhibition: a target for antifungal agents. Acta Biochim Pol 1995; 42:465-479.
47. Leaver DJ. Synthesis and biological activity of sterol 14α-demethylase and sterol C24-methyltransferase inhibitors. Molecules 2018; 23: E1753.
48. Nes WD. Enzyme mechanisms for sterol C-methylations. Phytochemistry 2003; 64: 75-95.
49. Lorente SO, Rodriques JCF, Jimenez-Jimenez C, Joyce-Menekse M, Rodriques C, Croft SL, et al. Novel azasterols as potential agents for treatment of leishmaniasis and trypanosomiasis. Antimicrob Agents Chemother 2004; 48:2937-2950.
50. Nes WD, Zhou W, Ganapathy K, Liu J, Vatsyayan R, Chamala S, et al. Sterol 24-C-methyltranferase: An enzymatic target for the disruption ofergosterol biosynthesis and homeostasis in Cryptococcus neoformans. Arch Biochem Biophys 2009; 481: 210-218.
51. Ragsdale NN, Sisler HD. Inhibition of ergosterol synthesis in Ustilago maydis by the fungicide triarimol. Biochem Biophys Res Commun 1972; 46: 2048-2053.
52. Van den Bossche H, Willemsens G, Cools W, Lauwers WFJ, Jeune Le, Chem L. Biochemical effects of miconazole on fungi. II. Inhibition of ergosterol biosynthesis in Candida albicans. Chem Biol Interact 1978; 21: 59-78.
53. Da Silva Ferreira ME, Colombo AL, Paulsen I, Ren Q, Wortman J, Huang J, et al. The ergosterol biosynthesis pathway, transporter genes, and azole resistance in Aspergillus fumigatus. Med Mycol 2005; 43 Suppl 1:S313-319.
54. Ruan B, Lai PS, Yeh CW, Wilson WK, Pang J, Xu R, et al. Alternative pathways of sterol synthesis in yeast. Use of C27 sterol tracers to study aberrant double-bond migrations and evaluate their relative importance. Steroids 2002; 67: 1109-1119.
55. Debeljak NA, Fink M, Rozman D. Many facets of mammalian lanosterol 14α-demethylase from the evolutionarily conserved cytochrome P450 family CYP51. Arch Biochem Biophys 2003; 409: 159-171.
56. Lepesheva GI, Waterman MR. Sterol 14α-demethylase cytochrome P450 (CYP51), a P450 in all biological kingdoms. Biochim Biophys Acta 2007; 1770: 467-477.
57. Favre B, Didmon M, Ryder NS. Multiple amino acid substitutions in lanosterol 14alpha-demethylase contribute to azole resistance in Candida albicans. Microbiology 1999; 145: 2715-2725.
58. Lamb DC, Kelly DE, White TC, Kelly SL. The R467K amino acid substitution in Candida albicans sterol 14α-demethylase causes drug resistance through reduced affinity. Antimicrob Agents Chemother 2000; 44: 63-67.
59. Nes WD, McCourt BS, Zhou W, Ma J, Marshall JA, Peek L, et al. Overexpression, purification, and stereochemical studies of the recombinant (S)-adenosyl-L-methionine: Δ24(25)- to Δ24(28)-sterol methyl transferase enzyme from Saccharomyces cerevisiae. Arch Biochem Biophys 1998; 353: 297-311.
60. Alicia L, Jialin L, Gamal A, Emily K, Kalgi S, Chizaram A, et al. Sterol C24-methyltransferase: Physio- and stereo-chemical features of the sterol C3 group required for catalytic competence. Arch Biochem Biophys 2012; 521: 43-50.
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.