Citrus Flavonoids as Antimicrobials

Abstract

Citrus flavonoids are highly bioactive compounds exerting numerous health benefits including anticancer, antioxidant, antimicrobial, anti-inflammatory, mitoprotective, and neuroprotective activity. Research on their broad-scope bioactivity experienced a renaissance in the early 2000s, and further accelerated after COVID-19, including research on their antimicrobial properties. Summarizing selected research achievements on the antimicrobial activity of the main Citrus flavonoids, this study aims to provide a unified picture on the antimicrobial properties of these valued compounds that will hopefully assist in the development of flavonoid-based antimicrobials, including antibacterial treatments suitable for clinical use minimizing antimicrobial resistance.

Keywords: antimicrobial resistance; citrus flavonoids; diosmin; hesperidin; naringenin; polymethoxyflavones.

FIGURE 1

Flavonoid general structure (top). Flavonoid structures organized by their families. Adapted from [15], Creative Commons Attribution (CC BY) license.

FIGURE 2

Documents by year dealing with “citrus flavonoids” indexed by research database Scopus between 1954 and late 2024. Created with data from scopus.com, with kind permission.

FIGURE 3

Chemical structures of naringenin (left) and naringin.

FIGURE 4

(A) Bacterial levels in the bones of mice from four experimental groups were determined. (B–E) Enzyme‐linked immunosorbent assay was performed to measure the levels of interleukin‐6 (B), IL‐1β (C), C‐reactive protein (D), and tumor necrosis factor‐α (E) in the femurs from each group. Reproduced from [22], with kind permission from John Wiley and Sons, 2024.

FIGURE 5

5 Chemical structures of nobiletin (left) and tangeretin.

FIGURE 6

SEM (A–C) and TEM (D–F) photographs showing the effect of nobiletin and tangeretin on morphology of Pseudomonas aeruginosa cells. Reproduced from [25], with kind permission from Elsevier, 2012.

FIGURE 7

Antifungal activity of individual pure flavonoid compounds against four phytopathogens at 0.1 mM (A, Sclerotinia sclerotiorum; B, Fusarium oxysporum f. sp. cucumerinum; C, Botrytis cinerea; D, Penicillium digitatum). Reproduced from [27], Creative Commons Attribution 4.0 International License from The Authors, 2021.

FIGURE 8

Photos of cucumber seedlings under four treatments after 20 days of cultivation in the greenhouse. Healthy group: cucumber seedlings without any treatment; disease group: cucumber seedlings inoculated with a fungal pathogen Fusarium oxysporum f. sp. cucumerinum and treated with sterilized water; negative group: cucumber seedlings inoculated with the pathogen and treated with empty microcapsules (microcapsules without flavonoid extracts); positive group: cucumber seedlings inoculated with the pathogen and treated with citrus flavonoid microcapsules. Reproduced from [27], Creative Commons Attribution 4.0 International License from The Authors, 2021.

FIGURE 9

Chemical structures of hespiridin (left) and hesperetin.

FIGURE 10

Microbial cells and in culture broth in the presence of hesperetin, hesperidin, and hesperidin glucoside. Reproduced from [32], Creative Commons Attribution (CC BY) license from The Authors, 2022.

FIGURE 11

Microbial transformation of hesperidin established in 2023. Reproduced from [33], Creative Commons Attribution (CC BY) license from The Authors, 2023.

FIGURE 12

Chemical structure of kaempferol.

FIGURE 13

(A) Scheme of the experimental procedures of mice pulmonary infection by Streptococcus pneumoniae. (B) Bacterial burden in the lungs of mice (n = 6 per group) determined by microbiological plating. (C) Pathological observation of lungs in different groups were evaluated by H&E staining. Scale bar = 100 and 200 µm *p < 0.05. [Copyright:  Reproduced from [41] with kind permission from Institut Pasteur, 2022. Published by Elsevier Masson SAS.

FIGURE 14

Chemical structures of rutin (left) and its aglycone quercetin (3,3,4,5,7‐pentahydroxiflavone).

FIGURE 15

Chemical structures of eriocitrin (left) and eriodictyol.

FIGURE 16

Chemical structures of apigenin (left) and apigenin‐7‐O‐glucoside (right).

FIGURE 17

Vicenin‐2 on PI3K, AKT, and PTEN signaling in Helicobacter pylori‐infected GES‐1 cells. (A) Western blot analysis of PI3K, AKT, and PTEN expression in vicenin‐2 and/or H. pylori‐infected GES‐1 cells; β‐actin was used as a normal loading control. (B) The quantification of protein was performed by densitometric analysis using ImageJ software. The densitometry data represent means ± SD from three immunoblots and are shown as the comparative density of protein bands normalized to β‐actin. Values not sharing common marking differ significantly at ^*,# p ≤ 0.05 (Duncan's multiple range test). AKT, protein kinase B; PI3K, phosphatidylinositol 3‐kinase; PTEN, phosphatase and tensin homolog. Reproduced from [49], with kind permission.

FIGURE 18

Chemical structures of diosmin.

FIGURE 19

Representative CLSM images of Pseudomonas aeruginosa PAO1 biofilms in control conditions (A–D) and after treatment with diosmin (E–H), myricetin (I–L), and neohesperidin (M–P). Bar = 25 µm for A, B, C, E, F, G, I, J, K, M, N, and O; bar = 10 µm for D, H, L, and P. Reproduced from [53], Creative Commons Attribution (CC BY) license from The Authors, 2024.

FIGURE 20

Protective effect of diosmin on survival of embryos after 18, 24, and 48 h post infection (hpi, A, B and C, respectively) with Pseudomonas aeruginosa PAO1 (mean ± SE): ctrl—control group; ictrl—control group with injured tail; B1—10⁷ CFU/mL; B2—10⁶ CFU/mL; M—MIC (0.1 mg/mL); 2M—2 MIC (0.2 mg/mL); str—streptomycin (10 µg/mL). Reproduced from [53], Creative Commons Attribution (CC BY) license from The Authors, 2024.

FIGURE 21

Mechanism of action of lemon IntegroPectin films against Gram‐negative bacterial strains: (A) disruption of membrane with consequent leakage of macromolecules in the extracellular environment, (B) targeting of enzymes crucial for cell functioning and vitality, (C) ROS production, (D) inhibition of efflux pumps, (E) acidification of the cytoplasm and protein denaturation, (F) intercalation with the DNA double helix, (G) permeabilization of the bacterial membrane, and (H) inhibition of ATP synthase. Reproduced from [62], Creative Commons Attribution (CC BY) license, from The Authors, 2022.