Abstract
Cordyceps is a genus of ascomycete fungi widely used in old Chinese medicine, and many investigations have focus on uncovering their biological activities. Until now, only a few compounds have been identified from Cordyceps, mainly due to their poor yield. So as to make full use of Cordyceps, we used the strategy of genome mining and heterologous expression to discover natural products (NPs) from Cordyceps militaris. Analysis of the genome sequence of Cordyceps militaris CM01 showed the presence of a cryptic gene cluster encoding a highly-reducing polyketide synthetase (HR-PKS), enoyl-reductase (ER) and cytochrome P450. Heterologous expression in Aspergillus nidulans enabled the identification of two new polyketides, cordypyrone A and B. Their structures were determined by 1D and 2D NMR techniques. They showed only modest activities against pathogenic bacteria including methicillin-resistant Staphylococcus aureus (MRSA), Mycobacteria tuberculosis and Bacillus cereus.
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References
Refaz Ahmad Dar*MS, Saika Rasool, Parvaiz Hassan Qazi. Natural product medicines: a literature update. J Phytopharmacology. 2017;6:340–2.
Jiang Z-D, An Z Bioactive fungal natural products through classic and biocombinatorial approaches. In: Atta ur R (ed). Studies in natural products chemistry, vol. 22. Elsevier, New York, 2000, pp 245-72.
Newman DJ, Cragg GM. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. J Nat Prod. 2020;83:770–803.
Butler MS, Robertson AA, Cooper MA. Natural product and natural product derived drugs in clinical trials. Nat Prod Rep. 2014;31:1612–61.
Kinghorn AD, DEB EJ, Lucas DM, Rakotondraibe HL, Orjala J, Soejarto DD, et al. Discovery of anticancer agents of diverse natural origin. Anticancer Res. 2016;36:5623–37.
Doostparast Torshizi A, Wang K. Next-generation sequencing in drug development: target identification and genetically stratified clinical trials. Drug Discov Today. 2018;23:1776–83.
Brakhage AA, Schroeckh V. Fungal secondary metabolites—strategies to activate silent gene clusters. Fungal Genet Biol. 2011;48:15–22.
Medema MH, Kottmann R, Yilmaz P, Cummings M, Biggins JB, Blin K, et al. Minimum Information about a biosynthetic Gene cluster. Nat Chem Biol. 2015;11:625–31.
Bachmann BO, Van Lanen SG, Baltz RH. Microbial genome mining for accelerated natural products discovery: is a renaissance in the making? J Ind Microbiol Biotechnol. 2014;41:175–84.
Chen R, Zhang Q, Tan B, Zheng L, Li H, Zhu Y, et al. Genome mining and activation of a silent PKS/NRPS gene cluster direct the production of totopotensamides. Org Lett. 2017;19:5697–5700.
Lin X, Yuan S, Chen S, Chen B, Xu H, Liu L, et al. Heterologous expression of Ilicicolin H biosynthetic gene cluster and production of a new potent antifungal reagent, Ilicicolin J. Molecules. 2019;24:2267.
Gao DW, Jamieson CS, Wang G, Yan Y, Zhou J, Houk KN, et al. A polyketide cyclase that forms medium-ring lactones. J Am Chem Soc. 2021;143:80–84.
Zhang JM, Wang HH, Liu X, Hu CH, Zou Y. Heterologous and engineered biosynthesis of nematocidal polyketide-nonribosomal peptide hybrid macrolactone from extreme thermophilic fungi. J Am Chem Soc. 2020;142:1957–65.
Velten R, Josten I, Steglich W. Ungesättigte 6-Alkylpyrone aus dem Schleimpilz Ceratiomyxa fruticulosa (Myxomycetes). Liebigs Ann. 1995;1995:81–85.
Brian PW, Curtis PJ, Hemming HG, Unwin CH, Wright JM. Alternaric acid, a biologically active metabolic product of the fungus Alternaria solani. Nature. 1949;164:534–534.
Fujii I, Yoshida N, Shimomaki S, Oikawa H, Ebizuka Y. An iterative type I polyketide synthase PKSN catalyzes synthesis of the decaketide alternapyrone with regio-specific octa-methylation. Chem Biol. 2005;12:1301–9.
Fairlamb IJ, Marrison LR, Dickinson JM, Lu FJ, Schmidt JP. 2-pyrones possessing antimicrobial and cytotoxic activities. Bioorg Med Chem. 2004;12:4285–99.
Wang X, Gao YL, Zhang ML, Zhang HD, Huang JZ, Li L. Genome mining and biosynthesis of the Acyl-CoA:cholesterol acyltransferase inhibitor beauveriolide I and III in Cordyceps militaris. J Biotechnol. 2020;309:85–91.
Li L, Yu P, Tang M-C, Zou Y, Gao S-S, Hung Y-S, et al. Biochemical characterization of a eukaryotic decalin-forming diels-alderase. J Am Chem Soc. 2016;138:15837–40.
Balouiri M, Sadiki M, Ibnsouda SK. Methods for in vitro evaluating antimicrobial activity: a review. J Pharm Anal. 2016;6:71–79.
Zheng P, Xia Y, Xiao G, Xiong C, Hu X, Zhang S, et al. Genome sequence of the insect pathogenic fungus Cordyceps militaris, a valued traditional chinese medicine. Genome Biol. 2011;12:R116.
Bumpus SB, Magarvey NA, Kelleher NL, Walsh CT, Calderone CT. Polyunsaturated fatty-acid-like trans-enoyl reductases utilized in polyketide biosynthesis. J Am Chem Soc. 2008;130:11614–6.
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This research was funded by the National Natural Science Foundation of China (31870039) and Natural Science Foundation of Fujian Province (2018J01727).
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Gao, YL., Yu, C. & Li, L. Heterologous expression of a natural product biosynthetic gene cluster from Cordyceps militaris. J Antibiot 75, 16–20 (2022). https://doi.org/10.1038/s41429-021-00478-3
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DOI: https://doi.org/10.1038/s41429-021-00478-3