Metabolomics and network pharmacology reveal antibacterial components and mechanisms in citrus herbs
Main Article Content
Keywords
Citrus herbs; antibacterial activity; metabolomics; network pharmacology
Abstract
This study evaluated the potential antibacterial activity and chemical profiles of four citrus herbs: Chenpi (CP),
Qingpi (QP), Zhike (ZK), and Zhishi (ZS). The total flavonoid content was significantly higher in the QP extract
compared to CP, as well as in the ZK extract compared to ZS. Additionally, the QP extract demonstrated stronger
antibacterial activity than the CP extract with a minimum inhibitory concentration (MIC) of 2.5 mg/mL against
both Bacillus cereus and methicillin-resistant Staphylococcus aureus (MRSA). Similarly, the ZK extract exhibited greater potency than ZS, exhibiting MICs of 1.25 mg/mL against B. cereus and 2.5 mg/mL against MRSA.
Metabolomic analysis revealed variations in the concentration of chemical compounds among the four citrus herb
extracts. Notably, (−)-quinic acid levels were significantly elevated in the QP extract compared to the CP extract.
The ZK extract showed markedly higher concentrations of key flavonoids, including hesperidin, naringin, and
hesperetin 7-O-neohesperidoside, relative to ZS. The upregulated accumulated metabolites in the QP and ZK
extracts were analyzed using network pharmacology to predict their potential antibacterial targets against bacterial infections. Core targets associated with bacterial infections, including TNF, MMP2, and AKT1, were identified. These findings highlight citrus herbs, particularly QP and ZK, as promising antibacterial candidates.
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Cebi, N. and Erarslan, A., 2023. Determination of the antifungal, antibacterial activity and volatile compound composition of citrus bergamia peel essential oil. Foods 12(1): 203. https://doi.org/10.3390/foods12010203
Chen, L., Zhao, N., Cao, J., Liu, X., Xu, J., Ma, Y., et al., 2022. Short- and long-read metagenomics expand individualized structural variations in gut microbiomes. Nature Communications 13: 3175. https://doi.org/10.1038/s41467-022-30857-9
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Ciriminna, R., Petri, G.L., Angellotti, G., Luque, R., Fabiano Tixier, A.S., Meneguzzo, F., et al., 2025. Citrus flavonoids as antimicrobials. Chemistry & Biodiversity 22(6): e202403210. https://doi.org/10.1002/cbdv.202403210
Cortés-Vieyra, R., Silva-García, O., Gómez-García, A., Gutiérrez-Castellanos, S., Álvarez-Aguilar, C., & Baizabal-Aguirre, V. M. (2021). Glycogen synthase kinase 3β modulates the inflammatory response activated by bacteria, viruses, and parasites. Frontiers in Immunology 12: 675751. https://doi.org/10.3389/fimmu.2021.675751
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D'Amore, T., Chaari, M., Falco, G., De Gregorio, G., Zaraî Jaouadi, N., Ali, D.S., et al., 2024. When sustainability meets health and innovation: The case of Citrus by-products for cancer chemoprevention and applications in functional foods. Biocatalysis and Agricultural Biotechnology 58: 103163. https://doi.org/https://doi.org/10.1016/j.bcab.2024.103163
Dimitrakopoulos, F.-I., Kottorou, A. and Tzezou, A., 2021. Endocrine resistance and epigenetic reprogramming in estrogen receptor positive breast cancer. Cancer Letters 517: 55–65. https://doi.org/https://doi.org/10.1016/j.canlet.2021.05.030
Duggal, S., Jailkhani, N., Midha, M.K., Agrawal, N., Rao, K.V.S. and Kumar, A., 2018. Defining the Akt1 interactome and its role in regulating the cell cycle. Scientific Reports 8(1),\: 1303. https://doi.org/10.1038/s41598-018-19689-0
Ellouze, I., Ben Akacha, B., Mekinić, I.G., Ben Saad, R., Kačániová, M., Kluz, M.I., et al., 2024. Enhancing antibacterial efficacy: Synergistic effects of Citrus aurantium essential oil mixtures against Escherichia coli for food preservation. Foods 13(19): 3093. https://doi.org/10.3390/foods13193093
Gao, Z., Gao, W., Zeng, S.-L., Li, P. and Liu, E.H., 2018. Chemical structures, bioactivities and molecular mechanisms of citrus polymethoxyflavones. Journal of Functional Foods 40: 498–509. https://doi.org/10.1016/j.jff.2017.11.036
García-López, C., Rodríguez-Calvo-de-Mora, M., Borroni, D., Sánchez-González, J.-M., Romano, V. and Rocha-de-Lossada, C., 2023. The role of matrix metalloproteinases in infectious corneal ulcers. Survey of Ophthalmolog 68(5): 929–939. https://doi.org/10.1016/j.survophthal.2023.06.007
Gómez, S., Querol-García, J., Sánchez-Barrón, G., Subias, M., González-Alsina, À., Franco-Hidalgo, V., et al., 2019. The antimicrobials anacardic acid and curcumin are not-competitive inhibitors of gram-positive bacterial pathogenic glyceraldehyde-3-phosphate dehydrogenase by a mechanism unrelated to human C5a anaphylatoxin binding. Frontiers in Microbiology 10: 326. https://doi.org/10.3389/fmicb.2019.00326
Guo, H., Chen, Y.-H., Wang, T.-M., Kang, T.-G., Sun, H.-Y., Pei, W.-H., et al., 2021. A strategy to discover selective α-glucosidase/acetylcholinesterase inhibitors from five function-similar citrus herbs through LC-Q-TOF-MS, bioassay and virtual screening. Journal of Chromatography B 1174: 122722. https://doi.org/10.1016/j.jchromb.2021.122722
Hao, X.-T., Peng, R., Guan, M., Zhang, H.-J., Guo, Y., Shalapy, N.M., et al., 2024. The food and medicinal homological resources benefiting patients with hyperlipidemia: categories, functional components, and mechanisms. Food & Medicine Homology 1(2): 9420003. https://doi.org/10.26599/fmh.2024.9420003
Impey, R.E., Hawkins, D.A., Sutton, J.M. and Soares da Costa, T.P., 2020. Overcoming intrinsic and acquired resistance mechanisms associated with the cell wall of Gram-negative bacteria. Antibiotics 9(9): 623. https://doi.org/10.3390/antibiotics9090623
Li, Y., Dalabasmaz, S., Gensberger-Reigl, S., Heymich, M.-L., Krofta, K. and Pischetsrieder, M., 2023. Identification of colupulone and lupulone as the main contributors to the antibacterial activity of hop extracts using activity-guided fractionation and metabolome analysis. Food Research International 169: 112832. https://doi.org/10.1016/j.foodres.2023.112832
Liu, H., Lin, J., Phan, Q.T., Bruno, V.M. and Filler, S.G., 2024. Epidermal growth factor receptor signaling governs the host inflammatory response to invasive aspergillosis. mBio 15: e0267124. https://doi.org/10.1128/mbio.02671-24
Liu, J., Liu, J., Tong, X., Peng, W., Wei, S., Sun, T., et al., 2021. Network pharmacology prediction and molecular docking-based strategy to discover the potential pharmacological mechanism of Huai Hua San against ulcerative colitis. Drug Design, Development and Therapy 15: 3255–3276. https://doi.org/10.2147/dddt.S319786
Liu, N., Li, X., Zhao, P., Zhang, X., Qiao, O., Huang, L., et al., 2021. A review of chemical constituents and health-promoting effects of citrus peels. Food Chemistry 365: 130585. https://doi.org/10.1016/j.foodchem.2021.130585
Liu, Z., Pan, Y., Li, X., Jie, J. and Zeng, M., 2017. Chemical composition, antimicrobial and anti-quorum sensing activities of pummelo peel flavonoid extract. Industrial Crops and Products 109: 862–868. https://doi.org/10.1016/j.indcrop.2017.09.054
Ma, A., Zou, F., Zhang, R. and Zhao, X., 2022. The effects and underlying mechanisms of medicine and food homologous flowers on the prevention and treatment of related diseases. Journal of Food Biochemistry 46(12): e14430. https://doi.org/https://doi.org/10.1111/jfbc.14430
Mannucci, C., Calapai, F., Cardia, L., Inferrera, G., D’Arena, G., Di Pietro, M., et al., 2018. Clinical pharmacology of Citrus aurantium and Citrus sinensis for the treatment of anxiety. Evidence-Based Complementary and Alternative Medicine 3624094: 1–18. https://doi.org/10.1155/2018/3624094
Maqbool, Z., Khalid, W., Atiq, H.T., Koraqi, H., Javaid, Z., Alhag, S.K., et al., 2023. Citrus waste as source of bioactive compounds: Extraction and utilization in health and food industry. Molecules 28(4): 1636. https://doi.org/10.3390/molecules28041636
Markazi, A., Meng, W., Bracci, P.M., McGrath, M.S. and Gao, S.-J., 2021. The role of bacteria in KSHV infection and KSHV-induced cancers. Cancers 13(17): 4269. https://doi.org/10.3390/cancers13174269
Mottaghipisheh, J., Taghrir, H., Boveiri Dehsheikh, A., Zomorodian, K., Irajie, C., Mahmoodi Sourestani, M., et al., 2021. Linarin, a glycosylated flavonoid, with potential therapeutic attributes: A comprehensive review. Pharmaceuticals 14(11): 1104. https://doi.org/10.3390/ph14111104
Neubert, P., Weichselbaum, A., Reitinger, C., Schatz, V., Schröder, A., Ferdinand, J. R., et al., 2019. HIF1A and NFAT5 coordinate Na+-boosted antibacterial defense via enhanced autophagy and autolysosomal targeting. Autophagy 15(11): 1899–1916. https://doi.org/10.1080/15548627.2019.1596483
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