Microbial Bioactives
Microbial Bioactives | Online ISSN 2209-2161
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Volume 9 Number 1 2026
REVIEWS (Open Access)
From Antioxidants to Enzyme Inhibitors: A Systematic Review and Meta-Analysis of Bioactive Natural Products Targeting Oxidative Stress, Mitochondrial Function, and Microbial Virulence
Feng Zhao 1*, Jiao Bai 2, Changjing Wu 3, Yanru Deng 4, Qingyun Peng 5,6, Weihao Chen 7, Jiao Xiao 2,8
Microbial Bioactives 9 (1) 1-8 https://doi.org/10.25163/microbbioacts.9110608
Submitted: 11 October 2025 Revised: 03 January 2026 Accepted: 12 January 2026 Published: 14 January 2026
Abstract
Natural products continue to serve as a foundational source of pharmacologically relevant molecules due to their chemical diversity and evolutionary optimization for biological interaction. This systematic review and meta-analysis synthesize current evidence on selected classes of bioactive natural products, including L-ascorbic acid and its derivatives, Annonaceous acetogenins, methylxanthines, butenolides, and marine-derived sesterterpenes, with a focus on their mechanistic actions and therapeutic potential. Emphasis is placed on compounds that modulate oxidative stress, mitochondrial bioenergetics, epigenetic regulation, and pathogen-specific metabolic pathways. Pharmacological concentrations of L-ascorbic acid demonstrate prooxidant activity that selectively induces cytotoxicity in cancer cells while also functioning as a cofactor for epigenetic enzymes involved in DNA demethylation. Annonaceous acetogenins, particularly chatenaytrienins, show potent inhibition of mitochondrial complex I, leading to reactive oxygen species generation and programmed cell death, although concerns regarding neurotoxicity remain. Marine suvanine sesterterpenes selectively inhibit isocitrate lyase in the glyoxylate cycle, a pathway essential for fungal virulence but absent in humans, highlighting a promising antivirulence strategy. Butenolide derivatives exhibit a wide spectrum of activities ranging from cytoprotection and cytoproliferation to antifungal and antibacterial effects, with structure–activity relationships guiding potency optimization. Quantitative synthesis of cytotoxicity and antifungal efficacy data supports the therapeutic relevance of these compounds while underscoring the importance of mechanistic specificity. Collectively, this review integrates biochemical, cellular, and computational evidence to evaluate the translational potential and limitations of these natural products in drug discovery.
Keywords: Natural products; butenolides; sesterterpenes; vitamin C; mitochondrial inhibition; isocitrate lyase; oxidative stress; antifungal agents
References
Antibiotics. (2016). Antibiotics: Technologies and global markets (PHM025D). BCC Research. https://www.bccresearch.com/market-research/pharmaceuticals/antibiotics-market-phm025c.html?srsltid=AfmBOoptB1ih2SOTDswqvyBPhQqyYpaYzKAvL9t3HhLkji0wAXkw9L_X
Bartlett, D. W., Clough, J. M., Godwin, J. R., Hall, A. A., Hamer, M., & Parr-Dobrzanski, B. (2002). The strobilurin fungicides. Pest Management Science, 58(7), 649–662. https://doi.org/10.1002/ps.520
Borenstein, M., Hedges, L. V., Higgins, J. P. T., & Rothstein, H. R. (2009). Introduction to meta-analysis. Wiley. https://doi.org/10.1002/9780470743386
Borenstein, M., Hedges, L. V., Higgins, J. P. T., & Rothstein, H. R. (2009). Introduction to meta-analysis. Wiley. https://doi.org/10.1002/9780470743386
Breijyeh, Z., Jubeh, B., & Karaman, R. (2020). Resistance of gram-negative bacteria to current antibacterial agents and approaches to resolve it. Molecules, 25(6), 1340. https://doi.org/10.3390/molecules25061340
Chan, B., Li, P., Tsang, M., Sung, J., Kwong, K., Zheng, T., Hon, S., Lau, C., Cheng, W., Chen, F., Lau, C., Leung, P., & Wong, C. (2023). Creating a vaccine-like supplement against respiratory infection using recombinant Bacillus subtilis spores expressing SARS-CoV-2 spike protein with natural products. Molecules, 28, 4996. https://doi.org/10.3390/molecules28134996
Chandra, P., Sharma, R. K., & Arora, D. S. (2020). Antioxidant compounds from microbial sources: A review. Food Research International, 129, 108849. https://doi.org/10.1016/j.foodres.2019.108849
Chen, G., Wen, D., Shen, L., Feng, Y., Xiong, Q., Li, P., & Zhao, Z. (2023). Cepharanthine exerts antioxidant and anti-inflammatory effects in lipopolysaccharide (LPS)-induced macrophages and DSS-induced colitis mice. Molecules, 28, 6070. https://doi.org/10.3390/molecules28166070
Cragg, G. M., & Newman, D. J. (2013). Natural products: A continuing source of novel drug leads. Biochimica et Biophysica Acta, 1830(6), 3670–3695. https://doi.org/10.1016/j.bbagen.2013.02.008
De Castro, I., Mendo, S., & Caetano, T. (2020). Antibiotics from haloarchaea: What can we learn from comparative genomics? Marine Biotechnology, 22, 308–316. https://doi.org/10.1007/s10126-020-09952-9
Degli Esposti, M. (1998). Inhibitors of NADH-ubiquinone reductase: An overview. Biochimica et Biophysica Acta, 1364(2), 222–235. https://doi.org/10.1016/S0005-2728(98)00029-2
Demain, A. L. (2014). Importance of microbial natural products and the need to revitalize their discovery. Journal of Industrial Microbiology & Biotechnology, 41, 185–201. https://doi.org/10.1007/s10295-013-1325-z
DerSimonian, R., & Laird, N. (1986). Meta-analysis in clinical trials. Controlled Clinical Trials, 7(3), 177–188. https://doi.org/10.1016/0197-2456(86)90046-2
Dzhemileva, L. U., Tuktarova, R. A., Dzhemilev, U. M., & D’yakonov, V. A. (2023). Natural acetogenins, chatenaytrienins-1, -2, -3 and -4, mitochondrial potential uncouplers and autophagy inducers—Promising anticancer agents. Antioxidants, 12(8), 1528. https://doi.org/10.3390/antiox12081528
Egger, M., Davey Smith, G., Schneider, M., & Minder, C. (1997). Bias in meta-analysis detected by a simple, graphical test. BMJ, 315(7109), 629–634. https://doi.org/10.1136/bmj.315.7109.629
Egger, M., Davey Smith, G., Schneider, M., & Minder, C. (1997). Bias in meta-analysis detected by a simple, graphical test. BMJ, 315(7109), 629–634. https://doi.org/10.1136/bmj.315.7109.629
Ekpe, L., Inaku, K., & Ekpe, V. (2018). Antioxidant effects of astaxanthin in various diseases—A review. Journal of Molecular Pathophysiology, 7, 1–6. https://doi.org/10.5455/jmp.20180627120817
Feng, T., & Wang, J. (2020). Oxidative stress tolerance and antioxidant capacity of lactic acid bacteria as probiotic: A systematic review. Gut Microbes, 12. https://doi.org/10.1080/19490976.2020.1801944
Fisher, N., & Meunier, B. (2008). Molecular basis of resistance to cytochrome bc1 inhibitors. FEMS Yeast Research, 8(2), 183–192. https://doi.org/10.1111/j.1567-1364.2007.00328.x
He, M., Liang, J., Shen, Y., Zhang, C., Yang, K., Liu, L., Xie, Q., Hu, C., Song, X., & Wang, Y. (2023). Coptisine inhibits influenza virus replication by upregulating p21. Molecules, 28, 5398. https://doi.org/10.3390/molecules28145398
Higgins, J. P. T., Thomas, J., Chandler, J., Cumpston, M., Li, T., Page, M. J., & Welch, V. A. (2022). Cochrane handbook for systematic reviews of interventions (Version 6.3). Cochrane. http://www.training.cochrane.org/handbook
Higgins, J. P. T., Thompson, S. G., Deeks, J. J., & Altman, D. G. (2003). Measuring inconsistency in meta-analyses. BMJ, 327(7414), 557–560. https://doi.org/10.1136/bmj.327.7414.557
Higgins, J. P. T., Thompson, S. G., Deeks, J. J., & Altman, D. G. (2003). Measuring inconsistency in meta-analyses. BMJ, 327(7414), 557–560. https://doi.org/10.1136/bmj.327.7414.557
Isman, M. B. (2006). Botanical insecticides, deterrents, and repellents in modern agriculture. Annual Review of Entomology, 51, 45–66. https://doi.org/10.1146/annurev.ento.51.110104.151146
Kumar, S., & Pandey, A. K. (2013). Chemistry and biological activities of flavonoids. The Scientific World Journal, 2013, 162750. https://doi.org/10.1155/2013/162750
Lin, J., Qu, Z., Pu, H., Shen, L., Yi, X., Lin, Y., Gong, R., Chen, G., & Chen, S. (2023). In vitro and in vivo anti-cancer activity of lasiokaurin in a triple-negative breast cancer model. Molecules, 28, 7701. https://doi.org/10.3390/molecules28237701
McLaughlin, J. L. (2008). Paw paw and cancer: Annonaceous acetogenins from discovery to commercial products. Journal of Natural Products, 71(7), 1311–1321. https://doi.org/10.1021/np800191t
Meyer, B. N., et al. (1982). Brine shrimp: A convenient general bioassay for active plant constituents. Planta Medica, 45(5), 31–34. https://doi.org/10.1055/s-2007-971236
Mishra, V., Shah, C., Mokashe, N., Chavan, R., Yadav, H., & Prajapati, J. (2015). Probiotics as potential antioxidants: A systematic review. Journal of Agricultural and Food Chemistry, 63, 3615–3626. https://doi.org/10.1021/jf506326t
Newman, D. J., & Cragg, G. M. (2016). Natural products as sources of new drugs from 1981 to 2014. Journal of Natural Products, 79(3), 629–661. https://doi.org/10.1021/acs.jnatprod.5b01055
Núñez-Montero, K., & Barrientos, L. (2018). Advances in antimicrobial drug discovery. Antibiotics, 7(3), 67. https://doi.org/10.3390/antibiotics7040090
Page, M. J., McKenzie, J. E., Bossuyt, P. M., Boutron, I., Hoffmann, T. C., Mulrow, C. D., et al. (2021). The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ, 372, n71. https://doi.org/10.1136/bmj.n71
Pisoschi, A. M., & Pop, A. (2015). The role of antioxidants in the chemistry of oxidative stress. European Journal of Medicinal Chemistry, 97, 55–74. https://doi.org/10.1016/j.ejmech.2015.04.040
Ralph, S. J., Rodríguez-Enríquez, S., Neuzil, J., Saavedra, E., & Moreno-Sánchez, R. (2010). The causes of cancer revisited. Molecular Aspects of Medicine, 31(2), 145–170. https://doi.org/10.1016/j.mam.2010.02.008
Ríos, J. L., & Recio, M. C. (2005). Medicinal plants and antimicrobial activity. Journal of Ethnopharmacology, 100(1–2), 80–84. https://doi.org/10.1016/j.jep.2005.04.025
Rodríguez-Cisneros, M., Morales-Ruíz, L., Salazar-Gómez, A., Rojas-Rojas, F., & Estrada-de los Santos, P. (2023). Compilation of the antimicrobial compounds produced by Burkholderia sensu stricto. Molecules, 28, 1646. https://doi.org/10.3390/molecules28041646
Sahoo, D. K., Wong, D., Patani, A., Paital, B., Yadav, V. K., Patel, A., & Jergens, A. E. (2024). Exploring the role of antioxidants in sepsis-associated oxidative stress: a comprehensive review. Frontiers in cellular and infection microbiology, 14, 1348713. https://doi.org/10.3389/fcimb.2024.1348713
Sarker, S. D., & Nahar, L. (2012). An introduction to natural products isolation. Methods in Molecular Biology, 864, 1–25. https://doi.org/10.1007/978-1-61779-624-1_1
Sen, T., Barrow, C. J., & Deshmukh, S. K. (2019). Microbial pigments in the food industry—Challenges and the way forward. Frontiers in Nutrition, 6, 7. https://doi.org/10.3389/fnut.2019.00007
Silver, L. L. (2011). Challenges of antibacterial discovery. Clinical Microbiology Reviews, 24(1), 71–109. https://doi.org/10.1128/CMR.00030-10
Singh, R., Kumar, M., Mittal, A., & Mehta, P. K. (2017). Microbial metabolites in nutrition, healthcare and agriculture. 3 Biotech, 7, 1–14. https://doi.org/10.1007/s13205-016-0586-4
Strobel, G., & Daisy, B. (2003). Bioprospecting for microbial endophytes. Microbiology and Molecular Biology Reviews, 67(4), 491–502. https://doi.org/10.1128/MMBR.67.4.491-502.2003
Tang, T., Li, S., Pan, B., Xiao, J., Pang, Y., Xie, S., Zhou, Y., Yang, J., & Wei, Y. (2023). Identification of flavonoids from Scutellaria barbata D. Don as inhibitors of HIV-1 and cathepsin L proteases and their structure–activity relationships. Molecules, 28, 4476. https://doi.org/10.3390/molecules28114476
Tormo, J. R., et al. (2003). Acetogenins as inhibitors of mitochondrial complex I. Bioorganic & Medicinal Chemistry Letters, 13(23), 4101–4105. https://doi.org/10.1016/j.bmcl.2003.08.045
Wallace, D. C. (2012). Mitochondria and cancer. Nature Reviews Cancer, 12(10), 685–698. https://doi.org/10.1038/nrc3365
Xu, M., Huang, Z., Zhu, W., Liu, Y., Bai, X., & Zhang, H. (2023). Fusarium-derived secondary metabolites with antimicrobial effects. Molecules, 28, 3424. https://doi.org/10.3390/molecules28083424
Young, A. J., & Lowe, G. L. (2018). Carotenoids—Antioxidant properties. Antioxidants, 7, 28. https://doi.org/10.3390/antiox7020028
Yu, R., Li, X., Yi, P., Wen, P., Wang, S., Liao, C., Song, X., Wu, H., He, Z., & Li, C. (2023). Isolation and identification of chemical compounds from Agaricus blazei Murrill and their in vitro antifungal activities. Molecules, 28, 7321. https://doi.org/10.3390/molecules28217321
Zhang, L., & Demain, A. L. (2005). Natural products and drug discovery. Natural Product Reports, 22(3), 352–356. https://doi.org/10.1007/978-1-59259-976-9
Zhang, Q., Li, Y., Zhao, B., Xu, L., Ma, H., & Wang, M. (2022). Synthesis and antifungal activity of new butenolide containing methoxyacrylate scaffold. Molecules, 27(19), 6541. https://doi.org/10.3390/molecules27196541
Zhao, J., Shan, T., Mou, Y., & Zhou, L. (2011). Plant-derived bioactive compounds produced by endophytic fungi. Mini-Reviews in Medicinal Chemistry, 11(2), 159–168. https://doi.org/10.2174/138955711794519492
Zhao, L., Xie, W., Du, Y., Xia, Y., Liu, K., Ku, C., Ou, Z., Wang, M., & Zhang, H. (2023). Isolation and anticancer progression evaluation of the chemical constituents from Bridelia balansae Tutcher. Molecules, 28, 6165. https://doi.org/10.3390/molecules28166165
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