A review: antimicrobial properties of several medicinal plants ...

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Review

A review: antimicrobial properties of several medicinal plants widely used in Traditional Chinese MedicineKun Chen (陈琨), Wei Wu (吴薇) , Xiudan Hou (侯秀丹), Qingli Yang (杨庆利)* and Zhaojie Li (李兆杰)*

College of Food Science and Engineering, Qingdao Agricultural University, Qingdao, China

*Corresponence to: Qingli Yang, College of Food Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China. E-mail: [email protected]; Zhaojie Li, College of Food Science and Engineering, Qingdao Agricultural University, Qing-dao 266109, China. E-mail: [email protected]

Received 5 April 2021; Revised 20 June 2021; Editorial decision 21 June 2021.

Abstract

Due to the dramatic increase in the use of antibiotics and growing health threat of bacterial resistance to many commonly used antibiotics, many studies have been directed at developing new and effective antibacterial compounds, among which many new, natural, and effective antibacterial compounds discovered from medicinal plants have drawn great interest and raised new hope for treating the challenges of antibiotic resistance. This review aimed to summarize the most important and widely used medicinal plants that were reported to have antibacterial activities. A general literature search from 2010 to 2020 was conducted using different databases, including Science Direct, Web of Science, and PubMed. According to the literature, three medicinal plants with outstanding antibacterial activities, Taraxacum officinale, Coptis Rhizome, and Scutellaria baicalensis, were screened and reviewed by prioritization. The extraction methods, antibacterial activities of different parts of plants or the plant-derived compounds, spectra of antibacterial activities, and toxicity were described, respectively. However, the antibacterial activities of the extracts or pure compounds as reported in the reviewed literature were mostly based on in vitro assays, and moreover, the deeper antibacterial mechanisms have not been elucidated clearly. Therefore, further studies are required in the fields of purification and identification of the antibacterial compounds, its mechanisms of action, and synergistic effects in combination with other antibacterial drugs, which may be helpful in the development of new antibacterial drugs.

Keywords: Medicinal plant; antibacterial activity; pathogenic bacteria; antibiotic resistance; antibacterial mechanism.

Introduction

Numerous infectious diseases, such as inflammatory bowel disease, irritable bowel syndrome, and colorectal cancer (Sell and Dolan, 2018), are caused by pathogenic bacteria each year worldwide, re-sulting in millions of deaths, and contributing significantly to the global burden of mortality (Jones et al., 2008). The majority of bac-terial diseases are due to intoxication or infection with Escherichia

coli (E. coli), Listeria monocytogenes (L. monocytogenes), Salmonella

typhimurium (S. typhimurium), Staphylococcus aureus (S. aureus),

Shigella dysenteriae, Mycobacterium tuberculosis, Bacillus cereus (B.

cereus), and Clostridium perfringens (Chen et al., 2017), which are

common foodborne pathogens. The discovery and development of

antibiotics have contributed to the cure of infectious diseases, and

significantly decreased the mortality rates of human around the

Food Quality and Safety, 2021, 5, 1–22https://doi.org/10.1093/fqsafe/fyab020

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world. Since their developments from the 1940s, antibiotics have be-come life-saving medicines that are integral to human health (Butler and Paterson, 2020).

However, the misuse or overuse of antibiotics has caused the increasing antibiotic resistance (AR) of pathogenic bacteria, which has become one of the greatest threats to public health (Chandra et al., 2017). The AR abilities of microorganisms can escape the effects of the drugs designed to kill or inhibit them by different mechanisms, such as neutralizing the antibiotics, pumping them outside of the cell, or modifying their outer structure, resulting in reducing the effects of drugs to the bacteria (Silhavy et al., 2010). Consequently, the use of these antibiotics is becoming increasingly restricted because of their toxicity possessed by themselves as well as their trickish AR. Despite all the efforts that have been devoted to combat AR on the national and international scale, this situation is still on the rise. Based on the 2019 report from the Centers for Disease Control and Prevention in the USA (Doînel et al., 1978), more than 2.8 million antibiotic-resistant infections occurred each year, and as a result, more than 35,000 people died. Therefore, there is an urgent and compelling need to develop new and effective anti-bacterial compounds with novel modes of action or as alternatives to antibiotics to address these serious problems. In early 2017, the World Health Organization (WHO) convened a group of experts that used a multicriteria decision analysis method to prioritize the need for new drugs to treat antibiotic-resistant bacteria (Tacconelli et al., 2018).

Several strategies have been reported to fight and control bac-terial AR, such as the development of new antimicrobial or auxiliary agents (Fang et al., 2019; Li et al., 2018; Zha et al., 2019; Zhao et al., 2019), structural modification of existing materials to synthe-size novel antibacterial compounds (Catto et al., 2010; Rakesh et al., 2018; Breijyeh et al., 2020), the synthesis of novel nanomaterials (Manukumar et al., 2017), and the study of novel targets that re-sistant bacteria are sensitive to (Chen et al., 2017; Qin et al., 2020). Another promising trend is by referring to nature to develop natur-ally derived agents with antibacterial activities.

Since ancient times, natural products have been utilized to treat a variety of human diseases, and have become a potential source of new therapeutic agents because of their unique and immense chem-ical diversity (Amedei and Niccolai, 2014). Ethnopharmacology, a multidisciplinary study of indigenous remedies, has great significance in the discovery of new drugs from natural sources (Holmstedt and Bruhn, 1983). The use of ‘medicinal plants’ has become a hotspot target of scientific research, because they are rich in active metab-olites with therapeutic properties, which shows promise for the de-velopment of new drugs (Yuan et al., 2016). According to the WHO (WHO,1997; Martinez et al., 2015), a medicinal plant is the plant in which one or more of their organs contain substances that can be used for therapeutic purposes or may be used as precursors in the synthesis of other drugs. More valuable, some of these medicinal plants are also economic vegetables, such as Solanaceae (Silalahi et al., 2014), dandelion (Astafieva et al., 2012), etc. They are as-sociated with advantages such as lower toxicity, economical, and multiple targets (Lin et al., 2016; Ma et al., 2019). It is well known that plants can develop different constitutive and inducible mechan-isms for the protection from pathogenic infection via morphological barriers, secondary metabolites, or antimicrobial peptides (AMPs; Benko-Iseppon et al., 2010). There are some natural medicinal com-pounds referred to as nonantibiotics from medicinal plants, which possess moderate to powerful antibacterial activities (Yuan et al., 2016), such as essential oils (Avonto et al., 2013; Lee et al., 2017),

berberine (Zhu et al., 2011; Sahibzada et al., 2018), allicin (Choo et al., 2020), antrographolide (Zhu et al., 2011; Wen et al., 2014), AMPs (Benko-Iseppon et al., 2010; Nawrot et al., 2014), and so on. These nonantibiotic drugs act in different manners on micro-bial growth. They may have direct antimicrobial activities (anti-microbial nonantibiotics), increase the efficacy of an antibiotic when coadministered (helper compounds), or change the pathogenicity of microorganisms or activity on the physiology, such as modulating macrophage activities (Martins et al., 2008).

In an era where it is becoming increasingly difficult to find new antibacterial drugs, it is very important to understand the antibac-terial activities of these medicinal plants comprehensively. After searching in the literature, we found the most recent articles referring to this topic. In this narrative review, we summarize the most im-portant and widely used medicinal plants that were reported to have antibacterial activities. A general literature search from 2010 to 2020 was conducted using different databases including Science Direct, Web of Science, and PubMed. According to the literature, three me-dicinal plants with antibacterial activities, Taraxacum officinale (T. officinale), Coptis rhizome (C. rhizome), and Scutellaria baicalensis (S. baicalensis), were screened and reviewed by prioritization. The antibacterial properties of each plant were detailed, including the extraction methods, antibacterial activities of different parts of the plant or the plant-derived compounds, spectra of antibacterial ac-tivities, toxicity, and so on. In addition, the possible mechanisms of action for the antibacterial activities of some of the extracts from the medicinal plants were described to a certain degree. The problems needing further study and prospects are discussed in this review.

Search Strategy and Data Extraction

According to the number of the publications about the plants with antibacterial activities during 2010–2020 (Figure 1), three plants were selected to detail in our review, i.e., T. officinale, C. rhizome, and S. baicalensis, which have obtained the most attention and are also widely applied in Traditional Chinese Medicine (TCM) or food.

Medicinal Plants With Antibacterial Activities

Taraxacum officinalePlants of the genus Taraxacum, which are members of the family Asteraceae and are widely distributed in the warmer temperate zones of the northern hemisphere, are perennial herbs and inhabit waste-lands, roadsides, and courtyards (Schütz et al., 2006a). According

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0 200 400 600 800 1000 1200

Coptis rhizomeTaraxacum officinale

Scutellaria baicalensisPrunus mumeFructus mume

Forsythia suspensaAngelica dahuricaFallopia japonica

Wolfiporia extensaPerilla frutescens

Amount of articles

Med

icin

al p

lants

Figure 1. The number of publications about medicinal plants with antibacterial activities

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to Kirschner et al. (2015), the genus includes about 60 sections with about 2800 species. Among all the species, T. officinale, Taraxacum mongolicum (T. mongolicum), Taraxacum laevigatum, Taraxacum kok-saghyz, and Taraxacum platycarpum are common kinds. In particular, T. officinale, known as the dandelion (Martinez et al., 2015), is the most widely studied and used.

Dandelion has been extensively used as a phytomedicine for its curative properties, and is included in the 2015 edition of the Chinese Pharmacopoeia (Liang et al., 2020). A large number of studies have demonstrated that dandelion has many pharmacological effects such as diuretic (Clare et al., 2009), antioxidant (Jędrejek et al., 2017; Jędrejek et al., 2019), antibacterial (Sengul et al., 2009; Sharifi-Rad et al., 2018), anti-inflammatory (Jeon et al., 2008; Hu et al., 2017), anticancer (Ovadje et al., 2016), hypoglycemic (Choi et al., 2018), hepatoprotective (Davaatseren et al., 2013; Cai et al., 2017), immune-enhancing (Lee et al., 2012; Tan et al., 2018), and so on. As we know, these functions are bound up with its constituents. It is reported that dandelion contains many active ingredients including sesquiterpene lactones (Kisiel and Barszcz, 2000; Jędrejek et al., 2019), phenolic acids (Budzianowski, 1997; Kisiel and Barszcz, 2000; Schütz et al., 2005), flavonoids (Kristó et al., 2002; Schütz et al., 2005), triterpenes (Akashi et al., 1994; Akihisa et al., 1996), coumarins (Budzianowski, 1997), polysaccharides (Cai et al., 2019; Guo et al., 2019; Wang et al., 2019), inulin (Schütz et al., 2006b), and sterols (Ivanov et al., 2018), which may contribute to these pharmacological effects. Among those, the characteristic of antibac-terial activity is one of the most important pharmacological effects. Interestingly, it is reported that the extracts from different parts of the dandelion exert various pharmacological effects including anti-bacterial activity, which is due to the existence of different active ingredients in these extracts.

Antibacterial activities of dandelionIt is true that extracts from different solvents possess different anti-bacterial activities, which are reflected in two aspects, namely, dif-ferent antibacterial spectra to different bacteria and different levels of antibacterial activity to the same bacterium. This makes sense because extracts from different solvents contain different active in-gredients. According to current reports, the common solvents used for extraction include hexane, ethyl acetate, methanol, chloroform, ethanol, and water, and even a combination of these solvents in ap-propriate proportions. The solvent extraction method is the most common method for the extraction of active compounds. Hydrogen peroxide hydrolysis, ultrasonic-assisted extraction, and enzyme-assisted extraction are usually used to extract active polysaccharides from dandelion.

The antibacterial activity of different parts of dandelion are detailed in this review. A summary of the antibacterial activity is presented in Table 1, and the profile of the antibacterial activity is shown in Figure 2.

Dandelion leavesThe hexane and ethyl acetate extracts were investigated for their antibacterial effects against several bacteria including E. coli, Proteus mirabilis (P. mirabilis), Klebsiella pneumoniae (K. pneumoniae) and S. aureus by broth serial dilution (Díaz et al., 2018). S. aureus was significantly inhibited by hexane extract at 200 μg/mL and the minimum inhibitory concentration (MIC) values were 400 μg/mL and 800 μg/mL for other bacteria, while ethyl acetate extracts only exhibited low antibacterial activity against E. coli, showing an

MIC of 1600 μg/mL, which was consistent with the study results of Ghaima et al. (2013). The main components of the extracts were identified by nuclear magnetic resonance (NMR) and gas chroma-tography–mass spectrometry (GC-MS). The hexane extracts mainly included lupeol acetate, betulin, lupeol, and 3,7,11,15-tetramethyl-2-hexadecen-1-ol, while the ethyl acetate extracts did not have lupeol. It was concluded by Díaz and colleagues that the presences of phenolic compounds, flavonoids, tannins, terpenes, alkaloids, and proteins in the extracts imparted the antibacterial property of dan-delion, which may act on the bacterial membrane (Díaz et al., 2018). To study the metabolite profile of dandelion, the authors employed N-hexane to separate the nonpolar constituents in dandelion leaves and a methanol:water (6:4) solution to distill the polar compositions of dandelion leaves; the extracts were then also analyzed by NMR and GC-MS (Grauso et al., 2019). The obtained results indicated that malic acid, malonic acid, myo-inositol, caffeoyl derivatives, and flavonoids were the specific polar materials with a high content ex-isting in the extract; besides, nonpolar ingredients were mainly com-posed of saturated fatty acid, such as palmitic acid, oleic acid, and stearic acid.

The antibacterial effects of methanol, chloroform, and water ex-tracts of dandelion leaves were also investigated. Sohail et al. (2014) utilized the agar well diffusion method to determine the inhibition zone diameter (IZD) of the extracts against four species of bacteria, E. coli, Bacillus subtilis (B. subtilis), S. aureus, and Pseudomonas aeruginosa (P. aeruginosa). The methanol extracts showed the highest antibacterial activities against S. aureus (13 mm), and chloroform extracts significantly inhibited E. coli (14 mm), while the water extracts had no activity against all test bacteria. It was found that all three extracts exerted no antibacterial effects on the Gram-negative bacteria of P. aeruginosa. Combined with other studies, it seemed that Gram-negative bacteria were usually more resistant to some active chemicals including antibiotics than Gram-positive bac-teria. For example, the same conclusions were obtained by Ghaima et al. (2013), who found that the ethyl acetate extracts of dandelion leaves gave a large IZD in B. cereus (18 mm), but showed poor anti-bacterial effects against E. coli and Salmonella typhi (S. typhi). The outer membrane of the Gram-negative bacterial cell wall, which acts as a barrier to many substances including antibiotics, contributes to the high tolerance of Gram-negative bacteria (Nikaido, 1994; Gao et al., 1999; Ghaima et al., 2013).

Additionally, many researchers used ethanol or water to extract the dandelion leaves, and investigated the antibacterial activities of the extracts. Specifically, it was found that 100 mg/mL and 200 mg/mL ethanol extracts had great inhibition on the growth of E. coli and S. aureus, and 50 mg/mL only inhibited E. coli (Adebayo and Issah, 2012), which was consistent with the previous research (Simsarian et al., 2011), while the water extracts were only active on E. coli at 100 mg/mL and 200 mg/mL. However, Jassim et al. (2012) proved that the alcohol extracts exhibited antibacterial activity against S. aureus, P. mirabilis, and E. coli at 0.5 mg/mL and 1 mg/mL, which were far lower than those above extracts, 100 mg/mL and 200 mg/mL. The water extracts had the same results except for no inhibition on E. coli at 0.5 mg/mL, which was also different from the results of Adebayo and Issah (2012). However, in another similar experiment, the water extracts of dandelion leaves did not show antibacterial activity against many common bacteria (Woods-Panzaru et al., 2009). Furthermore, a water solution of ethanol (40 per cent) was used as extract solvent to evaluate the antibacterial activity of dandelion leaves. It was shown that the extracts exhib-ited antibacterial activity against E. coli, while they had no effect on

Antimicrobial properties of several plants widely used in TCM 3

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Table 1. Summary of antibacterial activities of dandelion extracts

Parts of dandelion

Extract solvent Antibacterial activity Related mechanism Reference

Roots Methanol (2 mg/mL) S. aureus (MIC, 500 μg/mL) MRSA (MIC, 500 μg/mL) B. cereus (MIC, 500 μg/mL)

NR Kenny et al. (2015)

DCM (0.5 mg/50 μL) (1 mg/50 μL)

S. mutans (IZD, 21.00 mm and 22.00 mm) S. pyogenes (IZD, 28.67 mm and 29.00 mm) S. pneumonia (IZD, nil and nil) S. aureus (IZD, 24.00 mm and 26.33 mm) P. aeruginosa (IZD, nil and nil)

NR Amin et al. (2016)

Ethyl acetate (0.5 mg/50 μL) (1 mg/50 μL)

S. mutans (IZD, 18.00 mm and 20.33 mm) S. pyogenes (IZD, 24.33 mm and 24.67 mm) S. pneumonia (IZD, 21.75 mm and 22.67 mm) S. aureus (IZD, 25.00 mm and 25.79 mm) P. aeruginosa (IZD, nil and nil)

Methanol (0.5 mg/50 μL) (1 mg/50 μL)


Aqueous (0.5 mg/50 μL) (1 mg/50 μL)

S. mutans (IZD, 16.33 mm and 18.00 mm) S. pyogenes (IZD, 20.00 mm and 21.00mm) S. pneumonia (IZD, 17.00 mm and 19.33 mm) S. aureus (IZD, 20.33 mm and 22.67 mm) P. aeruginosa (IZD, nil and nil)

Water (2 mg/mL)

S. aureus (MIC, nil) MRSA (MIC, nil) B. cereus (MIC, nil) E. coli (MIC, nil) S. typhi (MIC, nil)

NR Kenny et al. (2014)

Ethanol (2 mg/mL)

S. aureus (MIC, 375 μg/mL) MRSA (MIC, 375 μg/mL) B. cereus (MIC, 500 μg/mL) E. coli (MIC, nil) S. typhi (MIC, nil)

Leaves Hexane E. coli (MIC, 400 μg/mL) S. aureus (MIC, 200 μg/mL) K. pneumoniae (MIC, 400 μg/mL) P. mirabilis (MIC, 800 μg/mL)

NR Díaz et al. (2018)

Ethyl acetate E. coli (MIC, 1600 μg/mL) S. aureus (MIC, nil) K. pneumoniae (MIC, nil) P. mirabilis (MIC, nil)

Methanol B. subtilis (IZD, 9.0 mm) S. aureus (IZD, 13.0 mm) E. coli (IZD, 10.0 mm) P. aeruginosa (IZD, 3.0 mm)

Secondary metabolites like alkaloids, tannins, and flavonoids might be responsible for anti-bacterial activity

Sohail et al. (2014)

Chloroform B. subtilis (IZD, 5.0 mm) S. aureus (IZD, 8.0 mm) E. coli (IZD, 14.0 mm) P. aeruginosa (IZD, 2.0 mm)

Distilled water B. subtilis (IZD, nil) S. aureus (IZD, nil) E. coli (IZD, nil) P. aeruginosa (IZD, nil)

Ethanolic (200 mg/mL) (100 mg/mL) (50 mg/mL)

E. coli (IZD, 23.50 mm, 16.00 mm, 10.50 mm) S. aureus (IZD, 10.75 mm, 9.00 mm, nil) K. pneumonia (IZD, nil, nil, nil) P. aeruginosa (IZD, nil, nil, nil)

NR Adebayo and Issah (2012)

Aqueous (200 mg/mL) (100 mg/mL) (50 mg/mL)

E. coli (IZD, 7.50 mm, 5.25 mm, nil) S. aureus (IZD, nil, nil, nil) K. pneumonia (IZD, nil, nil, nil) P. aeruginosa (IZD, nil, nil, nil)

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Parts of dandelion


Alcoholic (0.1 mg/mL) (0.5 mg/mL) (1 mg/mL)

S. aureus (IZD, nil, 4–10 mm, 4–10 mm) P. mirabilis (IZD, nil, 1–4 mm, 1–4 mm) E. coli (IZD, nil, 1–4 mm, 1–4 mm)

The leaf extracts had an active effect on the bac-terial cell membrane, and the inhibitory effects might be due to the presence of glycosides, phenolic com-pounds, tannins, flavon-oids, alkaloids, proteins

Jassim et al. (2012)

Water (0.1 mg/mL) (0.5 mg/mL) (1 mg/mL)

S. aureus (IZD, nil, 4–10 mm, 4–10 mm) P. mirabilis (IZD, nil, 1–4 mm, 1–4 mm) E. coli (IZD, nil, nil, 1–4 mm)

Ethyl acetate S. typhi (IZD, 14 mm) S. aureus (IZD, 16 mm) B. cereus (IZD, 18 mm) E. coli (IZD, 16 mm)

NR Ghaima et al. (2013)

Methanol:water 80:20 v/v (1st growing period of dandelion) (2nd growing period of dandelion)

B. cereus (MIC, 0.037 mg/mL, 0.20 mg/mL) S. aureus (MIC, 0.30 mg/mL, 0.90 mg/mL) L. monocytogenes (MIC, 0.30 mg/mL, 0.90 mg/mL) E. coli (MIC, 0.15 mg/mL, 0.30 mg/mL) S. typhimurium (MIC, 0.15 mg/mL, 0.60 mg/mL)

NR Petropoulos et al. (2019)

Flowers DCM (0.5 mg/50 μL) (1 mg/50 μL)








S. mutans (IZD, 14.00 mm and 16.33 mm) S. pyogenes (IZD, 20.33 mm and 21.33mm) S. pneumonia (IZD, nil and nil) S. aureus (IZD, 23.00 mm and 24.44 mm) P. aeruginosa (IZD, nil and nil)

Novel antibacterial peptides (ToAMP1) (ToAMP2) (ToAMP3)

P. syringae (IZD, 7 mm, 8 mm, 7 mm) B. subtilis (IZD, 5 mm, 3 mm, 3 mm)

NR Astafieva et al. (2012)

Stems DCM (0.5 mg/50 μL) (1 mg/50 μL)









Table 1. Continued


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S. aureus (Ionescu et al., 2013). In order to dissect the material base of the antibacterial action, the phytochemical constituents of the ethanol or water extracts of dandelion leaves were screened in these two researches above. In the study of Adebayo and Issah (2012), the extracts by ethanol and water did not contain flavonoids, which were detected in the extracts by ethanol in the study of Jassim et al. (2012). The same situation occurred with saponins.

It is well acknowledged that the biological functions of medicinal plants are bound up with their constituents, which is same for dande-lion and its antibacterial activity. It was reported that plant secondary metabolites, such as tannins, steroids, saponins, phenolic compounds, flavonoids, terpenes, alkaloids, glycosides, and peptides, play an im-portant role in antibacterial activity (Nweze et al., 2004; Astafieva et al., 2012; Díaz et al., 2018). These bioactive compounds show anti-bacterial effects through different mechanisms. For example, saponins have been reported to play a part in managing inflammation (Adebayo and Issah, 2012); tannins work by reacting with proteins has been proved to provide a tanning effect necessary for treating inflammation and inhibiting carrier enzymes and proteins in cell membranes (Kass and Seastone, 1944; Parekh and Chanda, 2007); alkaloids are able to interact with the DNA, and the phenolic compounds formed complex with dissolved protein out of the cells or with cell membranes to kill bacteria (Nikaido, 1994; Hu and Kitts, 2005; Jassim et al., 2012). In

other related reports, alpha-tocopherols were reported to destroy the efflux pumps of S. aureus to reduce resistance (Tintino et al., 2016), and organic acids were able to make the bacterial growth environment more acidic, and inhibit the formation of capsular polysaccharide of bacteria to exert antibacterial effects (Chen et al., 2011; Lin et al., 2013; Mitani et al., 2018). Therefore, it is understandable that ex-tracts from the same parts of dandelion by different solvents exhibit different antibacterial spectra, because they contain different active ingredients. Surprisingly, those researches show that extracts from the same parts exert different antibacterial spectra or a different degree of antibacterial activity to the same bacterium. The different extraction procedures and parameters or the bioassays performed may result in this disaccord.

The antibacterial activities of two growing periods of dande-lion (samples were collected on 17 October 2015 and 17 January 2016, respectively) against E. coli, L. monocytogenes, B. cereus, S. aureus, and S. typhimurium were carried out by the microdilution method, and dandelion was extracted by methanol:water (80:20 v/v; Petropoulos et al., 2019). Meanwhile, phenolic compounds, tocopherols, and organic acids of extracts were tested. The results indicated that the extracts from the two growing periods both sig-nificantly inhibited the growth of selected bacteria, and among them, B. cereus was the most sensitive bacteria, in agreement with

Parts of dandelion


Whole plants

Hydrogen peroxide B. subtilis (IZD, 12.04 mm) S. aureus (IZD, 16.15 mm) E. coli (IZD, 13.21 mm)

Dandelion-derived polysaccharides played the function

Qian et al. (2014)

Cellulase-assisted extraction

B. subtilis (IZD, 11.02 mm) S. aureus (IZD, 15.26 mm) E. coli (IZD, 12.47 mm)

Dandelion-derived polysaccharides played the function

Wang (2014)

B. cereus, Bacillus cereus; B. subtilis, Bacillus subtilis; DCM, dimethyl sulfoxide; E. coli, Escherichia coli; IZD, inhibition zone diameter; K. pneumonia, Kleb-siella pneumonia; MIC, minimum inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus; NR, no research; P. aeruginosa, Pseudomonas aeruginosa; P. mirabilis, Proteus mirabilis; P. syringae, Pseudomonas syringae; S. aureus, Staphylococcus aureus; S. mutans, Streptococcus mutans; S. pyogenes, Streptococcus pyogenes; S. pneumonia, Streptococcus pneumonia; S. typhi, Salmonella typhi; S. typhimurium, Salmonella typhimurium.

Table 1. Continued

Figure 2. The profile of antibacterial activities of Taraxacum officinale

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the results of Ghaima et al. (2013), while the MIC values of the first growing period were lower than the second, and dandelion had a better antibacterial effect in the first growing period. The composition analysis results showed that chicoric acids were the most abundant phenolic compounds, γ- and δ-tocopherols were the main tocopherols of dandelion, and oxalic acid was the amp-lest organic acid.

Except for direct use of dandelion leaf extracts for antibacterial activities, the methanolic extracts of dandelion leaves are used as a function of bio-inspired green synthesis for the fabrication of silver nanoparticles (AgNPs; Rasheed et al., 2017). Due to small size and large surface area characteristics of AgNPs, the generated AgNPs presented better antibacterial activity against S. aureus and E. coli than the extract itself, which provides a promising strategy for solving antibiotic resistance of bacteria.

Dandelion rootsThe antibacterial efficacies of crude and dialyzed extracts from dan-delion roots by several solvents were examined against three Gram-positive bacteria (S. aureus, methicillin-resistant Staphylococcus aureus (MRSA), and B. cereus) and two Gram-negative bacteria (E. coli and S. typhimurium; Kenny et al., 2015). The hexane ex-tracts exhibited antibacterial activities against B. cereus (MIC= 1000 μg/mL), the dimethyl sulfoxide (DCM) extracts inhibited S. aureus and MRSA (MICs=1000 μg/mL), and the methanol hydrophobic extracts were active against all three Gram-positive bacteria (MICs=500 μg/mL), while none of them showed inhib-ition on Gram-negative bacteria; similar results were reported by Amin et al. (2016) and Kenny et al. (2014). According to the re-search of Amin et al. (2016), dandelion roots were extracted by four solvents (DCM, ethyl acetate, methanol, and water; 0.5 mg/50 μL and 1 mg/50 μL), and the antibacterial properties of the extracts against five bacteria, including Streptococcus pyogenes (S. pyogenes), Streptococcus pneumoniae (S. pneumoniae), P. aeruginosa, S. aureus, and Streptococcus mutans (S. mutans), were tested by the agar well diffusion method. The DCM extracts had the maximum IZD against S. pyogenes (IZD, 28.67 mm and 29.00 mm) but showed no inhib-ition on S. pneumonia, while the other extracts all had antibacterial activities against S. pneumonia. Notably, P. aeruginosa was resistive to all extracts, but S. pyogenes and S. aureus were sensitive. Similarly, antibacterial effects of ethanol and water extracts of dandelion roots were investigated against three Gram-positive (B. cereus, MRSA, and S. aureus) and two Gram-negative (E. coli and S. typhimurium) strains (Kenny et al., 2014). Ethanol extracts showed significant inhib-ition on three Gram-positive bacteria with MIC values of 250 μg/mL and 375 μg/mL, while ethanol and water extracts did not inhibit the growth of Gram-negative strains. The water extracts contained sugars and glycosidic compounds, which might serve as a potential feed source to promote bacteria proliferation. In another study of Kenny and colleagues (Kenny et al., 2015), in order to further re-search the antibacterial activity of dandelion roots, the antibacterial activity of normal phase (NP) fractionations of methanol hydro-phobic extracts were also investigated.

As mentioned by Kenny et al. (2015), the further NP fraction-ations of NPF4 and NPF406 were identified by liquid chroma-tography solid-phase extraction NMR. The active compounds contained vanillin, coniferaldehyde, p-methoxyphenylglyoxylic acid, 9-hydroxyoctadecatrienoic acid, and 9-hydroxyoctadecadienoic acid. In the previous study (Kenny et al., 2014), Kenny and co-workers also studied the phenolic constituents of ethanol extracts by ultaperformance liquic chromatography–tandem mass spectrom-etry and found 11 kinds of phenolics, mainly including chlorogenic

acid, narirutin, pyrogallol, quinic acid, and luteolin, which may con-tribute to the antibacterial effects of dandelion. Sengul et al. (2009) also ascribed the antibacterial effects of the methanol extracts to phenolics, which was related to its antioxidant activities. However, the study results of López-García et al. (2013) were contrary to the above conclusions. Although there were phenolic compounds in the aqueous methanol (90 per cent, v/v) of dandelion flowers, the growth of S. aureus and E. coli was not inhibited.

Dandelion flowersAccording to the research of Amin et al. (2016), dandelion flowers were firstly extracted by four extraction solvents (DCM, ethyl acetate, methanol, and water; 0.5 mg/50 μL and 1 mg/50 μL), and the antibac-terial properties of extracts against five bacteria (S. pyogenes, S. pneu-monia, P. aeruginosa, S. aureus, and S. mutans) were carried out by the agar well diffusion method. The methanol extracts had the maximum inhibition zone diameter against S. pyogenes (IZD, 26.33 mm and 27.33 mm) and also exhibited antibacterial effects against S. mutans and S. aureus, while the ethanol extracts of dandelion flowers did not show any antibacterial effects against E. coli, S. aureus, P. aeruginosa, and B. subtilis (Khan et al., 2011). Besides, according to Amin et al. (2016), S. pyogenes and S. aureus were sensitive to the various extracts, while S. pneumonia and P. aeruginosa were resistive to all extracts. However, in another similar study (Qiao and Sun, 2014), the authors tested the antibacterial effects of ethanol extracts of T. mongolicum flowers and its fractions (petroleum ether, ethyl acetate, and water fractions) against E. coli, B. subtilis, S. aureus, Proteus vulgaris, and P. aeruginosa. The ethanol and ethyl acetate extracts showed signifi-cant inhibition on the growth of both Gram-negative and Gram-positive bacteria, especially B. subtilis and P. aeruginosa. On the other hand, petroleum ether and water fractions exhibited no antibacterial activity. Phytochemical compositions of ethanol and ethyl acetate extracts were similar, including flavonoids, terpenoids, and phen-olic acids, which may result in the antibacterial activities of extracts (Rantsev-Kartinov, 2005; Shi et al., 2008; Qiao and Sun, 2014). From the perspective of MIC, the ethyl acetate extracts showed lower MIC values than the ethanol extracts, and the ethyl acetate fractions were more effective against Gram-positive bacteria (lowest 62.5 μg/mL) compared to Gram-negative bacteria (lowest 125 μg/mL), which was perhaps a result of the barrier function of the cell membrane (Nikaido, 1994; Gao et al., 1999; Ghaima et al., 2013).

Three novel antibacterial peptides designated ToAMP1, ToAMP2, and ToAMP3 were purified from dandelion flowers, which were cat-ionic and cysteine-rich and consisted of 38, 44, and 42 amino acid residues, respectively (Astafieva et al., 2012). The peptides at 6 μg/μL produced a considerable antibacterial effect against Pseudomonas syringae (IZD, 7–8 mm) and B. subtilis (IZD, 3–5 mm).

Dandelion stemsAccording to the research of Amin et al. (2016), dandelion stems were extracted by four extraction solvents (DCM, ethyl acetate, methanol, and water; 0.5 mg/50 μL and 1 mg/50 μL, respectively) and the antibacterial properties of each extraction against five bacteria (S. pyogenes, S. pneumonia, P. aeruginosa, S. aureus, and S. mutans) were tested by the agar well diffusion method. The methanol extracts had the biggest inhibition zone diameter against S. aureus (IZD, 21.33 mm and 23.33 mm), and only the methanol extracts were active against S. pneumonia. However, P. aeruginosa was resistive to all stem extracts. Moreover, it was indicated that sesquiterpene lactones, triterpenes, phenolic acids, flavonoids, and coumarins might be the main active ingredients in the extracts of dandelion stems (González-Castejón et al., 2012).


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Comparison of different dandelion parts and various extrac-tion solvents may draw the following conclusions: roots are the most effective parts in inhibiting the growth of bacteria followed by flowers, while stems are the weakest parts. In addition, the methanolic extracts bear the highest antibacterial activity, following by ethyl acetate, DCM, and water. Different antibacterial potentials of various extracts indicate that the solvents could extract the dif-ferent active compounds varying in number. Moreover, in this study, the extracts of the plants extracted by highly polar organic solvents possessed higher antibacterial activity, which was also confirmed by Ionescu et al. (2013).

Whole dandelionDandelion was extracted by hydrogen peroxide to obtain oligo-saccharides, then the extraction conditions were optimized by response surface methodology to get the maximum yield of 25.43 per cent oligosaccharides (Qian et al., 2014). Antibacterial studies proved that oligosaccharides exhibited great antibac-terial effects against S. aureus (16.15 mm), E. coli (13.21 mm), and B. subtilis (12.04 mm). Polysaccharides could also be incorp-orated into nanomaterials to improve the antibacterial activity. A water-soluble antibacterial polysaccharide from dandelion (PD) was chemically modified to obtain its carboxymethylated derivative (CPD). The antibacterial effects of PD and CPD were studied by time-killing analysis and transmission electron micro-scope, and the results indicated that the numbers of residual L. monocytogenes decreased when treated with 10 mg/mL PD and CPD, and CPD had a greater antibacterial effect than PD; in addition, cell membrane and cell integrity of bacteria were des-troyed and CPD resulted in more severe damage. The enhanced antibacterial activities of CPD were attributed to the more stable triple-helical structures (Liu et al., 2017). Subsequently, PD and CPD were incorporated into a polyethylene oxide (PEO) nanofiber matrix to fabricate antimicrobial nanofibers and then their anti-bacterial effects were studied by the agar diffusion assay and the plate count method. The results indicated that there was a high efficiency of bacterial control for both PD/PEO and CPD/PEO nanofibers against L. monocytogenes. Moreover, T. laevigatum was also used for the synthesis of platinum nanoparticles (PtNPs), and the biosynthesized PtNPs exhibited great antibacterial effect against B. subtilis (15 mm) and P. aeruginosa (18 mm), and the MICs of PtNPs against B. subtilis and P. aeruginosa were 53.2 μg and 62.5 μg, respectively, which may be attributed to the small size, large surface area, uniform dispersion, and spherical morph-ology of PtNPs (Tahir et al., 2017).

In the research of Gao (2010), T. mongolicum was extracted by water and ethanol, and the water extracts showed no antibacterial effect and the ethanol extracts significantly inhibited the growth of E. coli (MIC, 50 μg/mL), P. aeruginosa (MIC, 100 μg/mL), and S. aureus (MIC, 50 μg/mL). As summarized by the author, phenylpropanoids and sesquiterpene lactones were the key to anti-bacterial activity and they were insoluble in water.

Dosage and toxicityDandelion extracts are listed on the U.S. Food and Drug

Administration’s ‘generally recognized as safe’ list for foods and sup-plements, which were found to pose little risk of harm (Yarnell and Abascal, 2009). The low toxicity is probably ascribed to the absence of any significant toxins or alkaloids (Schütz et al., 2006a).

In humans, dandelion is consumed as a kind of food and there-fore has a relatively low toxicity. The optimal daily dose of crude

dried roots or leaves of Taraxacum spp. is 4–10 g, while fresh roots or leaves can be consumed as food at levels of 50 g or more per day (Yarnell and Abascal, 2009).

In the USA, typical doses of root or leaf tinctures are 3–5 mL, 3 times per day, and the British Herbal Pharmacopoeia recommends 0.5–2 g of root or 4–8 mL of root tincture, 3 times per day (Yarnell and Abascal, 2009). In addition, the British Herbal Pharmacopoeia also advises 3–5 g of leaf or 5–10 mL of leaf tincture, 2 times per day. The German Commission E Monographs suggests doses of 3–4 g of root, 2 times per day, or 10–15 drops of tincture, 3 times per day (Blumenthal et al., 2000). The German Commission E Monographs proposes 4–10 g of leaf or 2–5 mL of tincture, 3 times per day (Blumenthal et al., 1998).

Dietary supplementation with dandelion extracts at 1 g/kg con-centration significantly improved intestinal immune ability and pro-moted intestinal development, as well as increased intestinal physical barrier of golden pompano (Tan et al., 2018). When rats and mice were administered the ethanolic extracts of dried dandelion at a dose of 10 g and 4 g of per kilogram body weight, the extracts exerted very low toxicity (Tita et al., 1993). Rabbits treated with 3–6 g/kg body weight of whole dried and powered dandelion plants showed no visible signs of acute toxicity (such as restlessness, respiratory distress, convulsions, coma, and death; Akhtar et al., 1985). Rats fed with diets containing 33 per cent dandelion for months showed no toxic effects (Hirono et al., 1978). No negative effects in humans have been reported during pregnancy or lactation, in children, or in combination with pharmaceutical drugs (Yarnell and Abascal, 2009).

ConclusionDandelion is an important TCM, which is usually extracted by methanol, ethanol, ethyl acetate, hexane, chloroform, and water to obtain phytochemicals, and is often handled by cellulase-assisted ex-traction and hydrogen peroxide hydrolysis to generate dandelion-derived polysaccharides. It is known that many factors affect antibacterial activity, such as extraction solvents, sources of dan-delion, the amounts of raw material, the extraction methods, and methods of test, which may result in the different antibacterial re-sults in the above researches. Through the review of dandelion, we can conclude carefully that dandelion roots extracts have a better antibacterial effect than other parts, and high polar organic solvents are the better choice to extract dandelion. Many kinds of bioactive compounds but not only one contribute to the antibacterial activities of dandelion, especially sesquiterpene lactones, flavonoids, phenolic acids, tannins, and alkaloids. Although it is demonstrated prelim-inarily that the bacterial cell membrane or DNA might be one of the targets of action, the known mechanisms of dandelion against pathogens are limited. Thus, commercial products of dandelion ac-tive compounds are still to be developed, and meanwhile, more ex-tensive and comprehensive studies are desperately needed to exploit unknown mechanisms.

Coptis rhizomeC. rhizome, also known as Huanglian in Chinese, is the rhizome of Coptis chinensis franch, which is commonly used as a main TCM to cure various diseases (Wang et al., 2019). In traditional Chinese remedy, more than 32 000 Chinese Medical Formulas mention C. rhizome, usually in the form of a powder, pill, decoction, or tablet (Wang et al., 2019).

Alkaloids are the main active compounds of C. rhizome, and they control the quality of C. rhizome (Han et al., 2019). Among

8 K. Chen et al.

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them, isoquinoline alkaloids account for a large percentage, with berberine as the most abundant composition. Common alkaloids include berberine, coptisine, palmatine, jatrorrhizine, epiberberine, magnoflorine, columbamine, oxyberberine, noroxyhydrastinine, 8-oxocoptisine, and berberubine (Huang et al., 2015; Qian et al., 2015). Among them, the five alkaloids of berberine, coptisine, palmatine, jatrorrhizine, and epiberberine share the same structural skeletons, which indicate their similar basic properties. The struc-tural differences among them are reflected in the different func-tional groups of C–2, C–3, C–9, and C–10, including –H, –CH2, and –CH3. Apart from alkaloids, C. rhizome also contains lignans, phenylpropanoids, flavonoids, phenolic compounds, saccharides, steroids, organic acids, quinones, and other chemical compounds (Gao et al., 2011; Meng et al., 2018).

By far the most numerous systematic research has led to the con-clusion that C. rhizome exerts potent pharmacological effects in various diseases (Gao et al., 2020) because of its antibacterial ac-tivity (Zhang et al., 2010), hypoglycemic action (Pan et al., 2019), anticancer effect (Liu et al., 2015), anti-inflammation function (Chen et al., 2017), lipid-lowering potential (Sun et al., 2017; Zhou et al., 2017), and anti-atherosclerotic potential (Hitt et al., 2017).

Antibacterial activities of C. rhizomeThe alkaloids of C. rhizome have been proved to be the main constituents against pathogens, and the antibacterial activities of different alkaloids are detailed in this part. A summary of the anti-bacterial activities is presented in Table 2, and the profile of the anti-bacterial activities is shown in Figure 3.

BerberineBerberine, with molecular formula C20H19NO5, a 5,6-dihydro-dibenzo [a,g] quinolizinium derivative, is an isoquinoline quaternary alkaloid from many kinds of medicinal plants. Berberine possesses multiple pharmacological effects, including antigastroenteritis, antidiabetic, anticancer activities, and so on. Of course, antibacterial activity is one of the most important.

It was reported that the absolute oral bioavailability of berberine was really low, while the concentration in liver was approximately 70-fold greater than in plasma (Liu et al., 2010), which attributed to liver organic cation transport and organic anion transporting poly-peptides (Chen et al., 2015). However, the various biological activities of berberine in vivo were achieved by the transformation of berberine into other active compounds through different metabolic pathways, mainly including sulfation, demethylation, reduction, methylation, demethylenation, and hydroxylation (Wang et al., 2017), or realized by the conversion of berberine into dihydroberberine via gut micro-biota (Feng et al., 2015).

MRSA has been an important hospital and community pathogen with multidrug resistance, the cause of the resistance being the genes located mainly in the mec region of the MRSA chromosome (Shiota et al., 1999). Berberine exhibited great antibacterial activity against all tested MRSA strains with MIC from 32 μg/mL to 128 μg/mL, and the possible action of berberine may be inhibition of the gene expression (Yu et al., 2005). As we know, bacterial adhesion and invasion into cells are one of the most common pathogenic mechan-isms, and it has been proved that berberine could block the adhesion of S. pyogenes and E. coli to host cells (Sun et al., 1988a, 1988b). Meanwhile, in the above studies, MRSA adhesion and intracellular invasion into human gingival fibroblasts were notably decreased in the presence of 1–50 μg/mL berberine. In another study, with

berberine at subminimum inhibitory concentrations (1–64 μg/mL), no antibacterial activity was found, but berberine could prevent ag-gregation of phenol-soluble modulins (PSMs) into amyloid fibrils in MRSA to inhibit the formation of biofilm by disrupting intermo-lecular attractions among PSM monomers and destabilizing the π–π stacking of phenylalanine residues (Chu et al., 2016).

After E. coli is exposed to berberine, it can form filaments, indicating the presence of inhibition of cell division. In order to test whether berberine inhibited cell division protein FtsZ, the effects of berberine on formation of the cell division Z-rings were tested (Boberek et al., 2010). The results showed a dramatic reduction in Z-rings in the presence of berberine, which contributed to antibac-terial actions. Besides, RNA silencing of ftsZ genes of E. coli resulted in increased sensitivity of bacteria to drugs, while overexpression of ftsZ genes led to a mild rescue effect in berberine-treated cells. Sun et al. (2014) designed and characterized berberine-based FtsZ inhibi-tors with broad-spectrum antibacterial activities.

A whole-genome DNA microarray was conducted to investigate the transcriptome analysis of Yersinia pestis (Y. pestis; Zhang et al., 2009) and Shigella flexneri (S. flexneri; Fu et al., 2010) in response to berberine. For Y. pestis, a total of 360 genes differentially changed: 333 genes were upregulated, involving genes related to energy me-tabolism, amino acid biosynthesis, degradation of macromolecules, and genes encoding cellular envelope and related to iron uptake, while 27 genes were downregulated. For S. flexneri, a total of 397 genes were disparately expressed, 164 genes were upregulated, such as genes associated with cell division, chromosome partitioning, translation apparatus, DNA replication and repair, cell envelope bio-genesis, and lipid metabolism, while 233 genes were downregulated, for example, genes concerned with energy production and conver-sion, amino acid metabolism, carbohydrate metabolism. The dif-ferences in results reflected the discrepant expression situation of metabolism genes. Most of the metabolism genes of Y. pestis were upregulated by berberine, while the metabolism genes of S. flexneri showed different changing trends. In another study (Du et al., 2020), quantitative proteomics was used to study the action mechanisms of berberine against S. pyogenes, which found similar conclusions to Fu et al. (2010). In addition, it was shown that reactive oxygen species were induced by berberine to damage macromolecular biosynthesis to trigger cell death. According to Yi et al. (2007), the metabolic profiles of S. aureus treated by berberine and 9 other antibacterial substances were obtained by high-performance liquid chromatog-raphy–mass spectrometry (HPLC-MS), and principal component analysis was carried out to investigate berberine’s possible antibac-terial modes. Results indicated that the antibacterial modes were similar to rifampicin and norfloxacin, which act on nucleic acid, such as RNA polymerase, gyrase, and topoisomerase IV.

Microcalorimetry, which has been used successfully to evaluate the effect of C. rhizome on microbial metabolism, was able to offer dynamic energy metabolism information with the flow of thermal effect and continuously recorded the signal for a long time without any system disturbance (Feng et al., 2011). It could be seen from heat flow power (HFP)–time curves that the growth metabolisms of Streptococcus dysenteriae were inhibited by berberine, and the max-imum HFP and total heat output were decreased with an increasing concentration of berberine (Kong et al., 2010). Meanwhile, microcalorimetry was used to investigate the effects of berberine on E. coli, B. subtilis, and their mixtures (Kong et al., 2012). A low concentration of berberine (20 μg/mL) could inhibit the growth of E. coli and the mixture of E. coli and B. subtilis. Interestingly, a low concentration of berberine could promote the growth of B. subtilis,


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Tab

le 2

. S

um

mar

y o

f an

tib

acte

rial

act

ivit

ies

of

alka

loid

s fr

om

C. r

hiz

om

e

Type

of

al

kalo

ids

Ext

ract

so

lven

tA

ntib

acte

rial

res

ult

Rel

ated

mec

hani

smR

efer

ence

Ber

beri

nePu

rcha

sed

MR

SA (

MIC

s, 3

2–12

8 μ

g/m

L)

M

RSA

(IZ

D, 1

7–26

mm

)

MR

SA O

MS7

(M

IC, 4

μg/

mL

) (3

2 μ

g/m

L b

erbe

rine

+am

pici

llin)

M

RSA

OM

S7 (

MIC

, 1 μ

g/m

L)

(32

μg/

mL

ber

beri

ne c

ombi

nes+

oxac

illin

) M

RSA

AT

CC

259

23 (

MIC

, 0.0

16 μ

g/m

L)

(64

μg/

mL

ber

beri

ne+a

mpi

cilli

n)

MR

SA A

TC

C 2

5923

(M

IC, 0

.008

μg/

mL

) (6

4 μ

g/m

L b

erbe

rine

+oxa

cilli

n)

Ber

beri

ne c

ould

inhi

bit

the

mec

reg

ion

of M

RSA

chr

omos

ome,

lo

wer

the

MIC

s of

am

pici

llin

and

oxac

illin

aga

inst

MR

SA, a

nd

decr

ease

MR

SA a

dhes

ion

and

intr

acel

lula

r in

vasi

on

Yu

et a

l. (2

005)

E

than

olSa

lmon

ella

str

ain

CV

CC

528

(MIC

, 312

5 μ

g/m

L)

M

ulti

resi

stan

t Sa

lmon

ella

str

ain

(MIC

, 312

5 μ

g/m

L)

M

ulti

resi

stan

t Sa

lmon

ella

str

ain+

cipr

oflox

acin

(M

IC, 1

562

μg/

mL

)

Ber

beri

ne c

ould

dec

reas

e th

e ex

pres

sion

s of

Lux

S, r

poE

, and

om

pR, w

hich

wer

e re

late

d to

the

for

mat

ion

of b

iofil

mSh

i et

al. (

2018

)

Pu

rcha

sed

E. c

oli s

trai

n K

-12

(RN

A s

ilenc

ing

of F

tsZ

) (M

IC, 1

.5 m

mol

/L)

Ber

beri

ne c

ould

inhi

bit

cell

divi

sion

pro

tein

Fts

Z, w

hich

was

d re

flect

ed in

dra

mat

ic r

educ

tion

in Z

-rin

gsB

ober

ek e

t al

. (20

10)

Pu

rcha

sed

Met

hod:

mic

roca

lori

met

ry

S. a

ureu

s:

berb

erin

e>co

ptis

ine>

palm

atin

e>ep

iber

beri

ne>j

atro

rrhi

zine

E

. col

i:

berb

erin

e>co

ptis

ine>

palm

atin

e B

. shi

gae,

E. c

oli:

be

rber

ine>

copt

isin

e>pa

lmat

ine

B. a

dole

scen

tis:

pa

lmat

ine>

copt

isin

e>be

rber

ine

E. c

oli:

be

rber

ine>

copt

isin

e>pa

lmat

ine>

jatr

orrh

izin

e

The

fun

ctio

nal g

roup

s m

ethy

lene

diox

y at

C–2

and

C–3

on

phen

yl r

ing

impr

oved

ant

ibac

teri

al a

ctiv

ity

mor

e re

mar

kabl

y th

an m

etho

xyl a

t C

–2 a

nd C

–3 o

n th

e ph

enyl

rin

g, w

hile

m

ethy

lene

diox

y or

met

hoxy

l at

C–9

and

C–-

10 d

id n

ot v

ary

sign

ifica

ntly

. Bes

ides

, ber

beri

ne m

ainl

y ac

ted

on h

arm

ful b

ac-

teri

a

Fan

et a

l. (2

008)

, Kon

g et

al.

(200

9), Y

an e

t al

. (2

008,

200

9)

Pu

rcha

sed

MR

SA (

MIC

, 128

μg/

mL

)B

erbe

rine

cou

ld a

ffec

t ph

enol

-sol

uble

mod

ulin

s ag

greg

atio

n in

to a

myl

oid

fibri

ls t

o in

hibi

t th

e bi

ofilm

for

mat

ion

of M

RSA

Chu

et

al. (

2016

)

Pu

rcha

sed

Met

hod:

mic

roca

lori

met

ry

S. d

ysen

teri

ae

E. c

oli

B. s

ubti

lis

NR

Kon

g et

al.

(201

0,

2012

)

Pu

rcha

sed

Tre

atm

ent

wit

h be

rber

ine

sign

ifica

ntly

incr

ease

d th

e su

rviv

al r

ate

of m

ice

chal

leng

ed w

ith

S. t

yphi

mur

ium

By

com

pari

ng w

ith

LPS

, ber

beri

ne c

ould

pre

sent

hig

her

affin

ity

to t

he T

LR

4/M

D-2

rec

epto

r to

red

uce

the

prod

ucti

on o

f in

-fla

mm

ator

y fa

ctor

s to

ach

ieve

ant

ibac

teri

al e

ffec

t

Chu

et

al. (

2014

)

Pu

rcha

sed

Met

hod:

HPL

C-M

S an

d pr

inci

pal c

ompo

nent

ana

lysi

s

S. a

ureu

sB

erbe

rine

mig

ht a

ct o

n nu

clei

c ac

id, s

uch

as R

NA

pol

ymer

ase,

gy

rase

, and

top

oiso

mer

ase

IVY

i et

al. (

2007

)

Pu

rcha

sed

H. p

ylor

i (M

ICs,

100

–200

μg/

mL

)B

erbe

rine

cou

ld in

hibi

t th

e ex

pres

sion

of

efflu

x pu

mp

hefA

m

RN

AH

uang

et

al. (

2015

)

Pu

rcha

sed

Met

hod:

a m

ulti

-om

ics

stud

y

E. c

oli

Ber

beri

ne c

ould

tri

gger

DN

A r

eplic

atio

n/re

pair

and

tra

nscr

ip-

tion

, des

troy

the

cel

l mem

bran

e an

d m

otili

ty-r

elat

ed f

unct

ions

, an

d re

pres

s ge

nes

of m

etab

olis

ms

Kar

aosm

anog

lu e

t al

. (2

014)

Pu

rcha

sed

MR

SA 4

806

(MIC

, 32

μg/

mL

, ber

beri

ne)

M

RSA

480

6 (M

IC, 1

024

μg/

mL

, fus

idic

aci

d)

MR

SA (

MIC

s, 0

.062

5–8

μg/

mL

, ber

beri

ne+f

usid

ic a

cid)

Ber

beri

ne c

ould

inhi

bit

the

biofi

lm f

orm

atio

n an

d de

stro

y m

a-tu

re b

iofil

mL

iang

et

al. (

2014

)

Pu

rcha

sed

MR

SA (

MIC

, 32–

128

μg/

mL

)N

RZ

uo e

t al

. (20

12)

10 K. Chen et al.

Dow



Type

of

al

kalo

ids

Ext

ract

so

lven

tA

ntib

acte

rial

res

ult

Rel

ated

mec

hani

smR

efer

ence

Cop

tisi

nePu

rcha

sed

H. p

ylor

i sta

ndar

d st

rain

(M

IC, 2

5 μ

g/m

L)

H

. pyl

ori s

trai

ns (

MIC

s, 2

5–50

μg/

mL

)C

opti

sine

cou

ld p

lay

the

anti

-H. p

ylor

i eff

ect

by in

hibi

ting

the

ac

tivi

ty o

f ur

ease

. Sul

fhyd

ryl g

roup

was

the

mai

n ac

tion

sit

e of

co

ptis

ine

in u

reas

e. C

opti

sine

inte

rfer

ed w

ith

urea

se m

atur

atio

n by

inhi

biti

ng a

ctiv

ity

of p

roto

typi

cal u

reas

e ac

cess

ory

prot

ein

Ure

G a

nd f

orm

atio

n of

Ure

G d

imer

s an

d by

pro

mot

ing

diss

oci-

atio

n of

nic

kel f

rom

Ure

G d

imer

s

Li e

t al

. (20

18)

Palm

atin

ePu

rcha

sed

H. p

ylor

i str

ains

(M

ICs,

100

–200

μg/

mL

, pH

7.4

)

H. p

ylor

i str

ains

(M

ICs,

75–

100

μg/

mL

, pH

5.3

)

Ure

ase

of H

. pyl

ori (

IC50

, 0.5

3 m

mol

/L)

The

inhi

biti

on o

f pa

lmat

ine

on t

he u

reas

e w

as r

ever

sibl

e an

d th

e su

lfhy

dryl

gro

ups

wer

e th

e m

ain

site

s of

act

ion

of

palm

atin

e. T

he m

olec

ular

doc

king

stu

dy p

rove

d th

at p

alm

atin

e in

tera

cted

wit

h su

lfhy

dryl

gro

ups

thro

ugh

N–H

=π in

tera

ctio

n

Zho

u et

al.

(201

7)

Epi

berb

erin

ePu

rcha

sed

Ure

ase

of H

. pyl

ori (

IC50

, 3.0

μm

ol/L

)T

he b

ond

of e

pibe

rber

ine

wit

h ur

ease

was

rev

ersi

ble

and

the

sulf

hydr

yl g

roup

s w

ere

the

mai

n ac

ting

poi

nts

by e

pibe

rber

ine.

A

s re

sear

ched

in m

olec

ular

doc

king

stu

dies

, 9-O

-CH

2 an

d 2-

O-

CH

3 of

epi

berb

erin

e fo

rmed

str

ong

N–H

≡O h

ydro

gen

bond

to

the

back

bone

wit

h th

e ba

ckbo

ne H

ato

m o

f M

et-3

66 a

nd A

sn-

168,

res

pect

ivel

y

Tan

et a

l. (2

017)

B. a

dole

scen

tis,

Bifi

doba

cter

ium

ado

lesc

enti

s; B

. shi

gae,

Bac

illus

shi

gae;

B. s

ubti

lis, B

acill

us s

ubti

lis; H

PLC

-MS,

hig

h-pe

rfor

man

ce li

quid

chr

omat

ogra

phy–

mas

s sp

ectr

omet

ry; I

C50

, hal

f m

axim

al in

hibi

tory

con

cent

rati

on;

IZD

, inh

ibit

ion

zone

dia

met

er; m

inim

um in

hibi

tory

con

cent

rati

on; M

RSA

, met

hici

llin-

resi

stan

t St

aphy

loco

ccus

aur

eus;

NR

, no

rese

arch

; C. r

hizo

me,

Cop

tis

rhiz

ome;

E. c

oli,

Esc

heri

chia

col

i; S.

aur

eus,

Sta

phyl

ococ

cus

aure

us;

S. d

ysen

teri

ae, S

hige

lla d

ysen

teri

ae; H

. pyl

ori,

Hel

icob

acte

r lip

opol

ysac

char

ide.

Tab

le 2

. C

on

tin

ued


Dow



while a high concentration (over 100 μg/mL) could inhibit it. Results showed that E. coli could decrease the endurance of B. subtilis to berberine and the growth characters of B. subtilis would not be pre-sent in their mixture, which might attribute to the inhibitory effects of E. coli on B. subtilis.

Lipopolysaccharide (LPS), a kind of endotoxin, triggers the signal transduction pathway leading to inflammatory reaction by binding to the TLR4/MD-2 receptor via hydrophobic interaction, and its immune activating abilities are attributed to the lipid A unit (Salomao et al., 2012; Lacatus, 2013). The survival rate of mice in-fected by S. typhimurium significantly improved after treatment with increasing concentration of berberine (Chu et al., 2014). In addition, berberine was able to reduce the mortality rate of mice challenged with LPS and delay their death time. Meanwhile, berberine treat-ment lowered the increasing body temperature of rabbits challenged with LPS. The molecular mechanism studies that followed showed that berberine presented higher affinity to the TLR4/MD-2 receptor to block the signaling in comparison with LPS.

With the increasing use of antibiotics and the emergence of bacterial drug resistance, much attention has been focused on traditional Chinese herbal medications in combination with anti-biotics to achieve drug synergy, enhance efficacy, and reduce tox-icity (Sharma et al., 2010). Berberine could significantly lower the MICs of antibiotics against MRSA; an additive effect was found be-tween berberine and ampicillin and a synergistic effect was found between berberine and oxacillin against MRSA (Yu et al., 2005); a synergistic action was found between fusidic acid and berberine against MRSA (Liang et al., 2014); synergies were observed for the berberine/azithromycin and berberine/levofloxacin combinations against MRSA; and an additivity result was observed for the ber-berine/azithromycin combination against MRSA (Zuo et al., 2012). Additionally, a synergistic inhibition effect was found between ber-berine and ciprofloxacin on the biofilm formation of a multiresistant Salmonella strain by repressing the expressions of luxS, rpoE, and

ompR mRNA (Shi et al., 2018). The different antibacterial results of berberine in combination with various antibiotics were attributed to the block of different bacterial resistance mechanisms, which was proved to be a promising approach to solve current antibacterial agents’ resistance (Zuo et al., 2012).

Li et al. (2019) designed two natural self-assembling modes using berberine and flavonoid glycosides: nanoparticles (NPs) and nanofibers (NFs); they first formed a one-dimensional complex unit and subsequently self-assembled into three-dimensional nanostructures. NPs with the hydrophilic glucuronic acid toward the outside exhibited significantly more antibacterial activity against S. aureus and biofilm removal ability than berberine, whereas NFs showed a weaker effect than berberine. In addition, self-assembled nanostructures had good biocompatibility proved by hemolysis tests, cytotoxicity tests, and zebrafish toxicity evaluation. The evaporative precipitation of nanosuspension (EPN) and antisolvent precipitation with a syringe pump (APSP) methods were used to synthesize ber-berine nanoparticles, respectively, which had increased solubility and dissolution rate by the conversion of the crystalline structure to a semicrystalline form (Sahibzada et al., 2018). Moreover, berberine NPs exhibited superior antibacterial activities against S. aureus, E. coli, P. aeruginosa, and B. subtilis, and NPs synthesized by the EPN method showed a better effect than those by the APSP method.

In addition, the aqueous extracts of C. rhizome were used to synthesize silver nanoparticles (Pei et al., 2019) and form nanofibers with poly(vinyl alcohol) (Yang et al., 2018). They were proved to exhibit significant antibacterial activities against B. subtilis, P. aeruginosa, S. aureus, and K. pneumoniae. Compared with the compounds themselves, the nanoparticles showed higher antibac-terial activities, which may be due to their size and large surface area.

CoptisineCoptisine, with the molecular formula C19H14NO4, derived from benzylisoquinolines through phenolic oxidation and coupling with

Figure 3. The profile of antibacterial effects of isoquinoline alkaloids from Coptis rhizome. LPS, lipopolysaccharide

12 K. Chen et al.

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the isoquinoline N-methyl group, is a typical quaternary proberberine alkaloid from C. rhizome (Wang et al., 2019). Coptisine possesses multiple pharmacological effects, including anticancer, antibacterial, anti-inflammatory effects, and so on (Wu et al., 2019).

Urease is critical to the colonization and virulence of Helicobacter pylori (H. pylori), and can catalyze the hydrolysis of urea to ammonia to create an alkaline local environment re-quired for the survival of H. pylori (Zeer-Wanklyn and Zamble, 2017). The binuclear nickel ions existing in the active site and sulfhydryl groups are essential for its catalytic activity (Krajewska and Zaborska, 2007; Kumar and Kayastha, 2010). Coptisine had remarkable antibacterial activities against H. pylori with MICs of 25–50 μg/mL, and urease inhibitory activities were achieved by binding to the urease active site sulfhydryl group and nickel metallocenter (Li et al., 2018). The H. pylori urease inhibition in-duced by coptisine was mixed-type. According to the reaction pro-gress curves of coptisine and urease, the binding process involved the rapid formation of a collision complex that then underwent a slow conversion into a more stable final complex. Additionally, after adding dithiothreitol, the activities of coptisine-inhibited urease were partially restored, which proved that coptisine-induced inhibition of urease was reversible.

As proved by in vivo study, coptisine interfered with urease maturation by inhibiting the activity of prototypical urease acces-sory protein UreG and the formation of UreG dimers, and by pro-moting dissociation of nickel form UreG dimers. Besides, according to molecular docking study, the coptisine 3–O–CH2– group formed hydrogen bond interactions with the NH group of His-221 at a distance of 2.2×10-10 m, and the benzene rings of coptisine might form hydrophobic interactions with Ala-169, Ala-365, Met-366, His-322, Cys-321, and His-323.

PalmatinePalmatine, with the molecular formula C21H22NO4, is a naturally occurring isoquinoline alkaloid found in many TCMs. Palmatine has many pharmacological functions, including neuroprotective, anticancer, antibacterial, anti-inflammatory effects, and so on (Long et al., 2019).

The MIC values of palmatine against 4 tested H. pylori strains were measured by the agar dilution test, and MIC values were 100–200 μg/mL and 75–100 μg/mL under neutral and acidic con-ditions, respectively, which proved the potential of palmatine acting as a beneficial therapy for H. pylori infection (Zhou et al., 2017). Urease inhibitory activity of palmatine was implemented by binding to the urease active site sulfhydryl group, and the inhibition process was reversible. Kinetic analyses indicated that the urease inhibition by palmatine was noncompetitive.

Further molecular docking research showed that palmatine in-hibited the active enzymatic conformation through N–H=π inter-action, but did not interact with the active site Ni2+, which was different to coptisine. From the docking conformation, 2-OCH3 of palmatine, which was the hydrogen bond donor, formed O–H≡N hydrogen bond (H≡N distance=2.1×10-10 m) to the OH and the backbone N atom of Arg-339 of the active site of the enzyme.

As summarized by previous articles (Thakur et al., 2016; Long et al., 2019), the potential antibacterial mechanisms of palmatine might involve insertion of bacterial DNA, inhibition of protein bio-synthesis, inhibition of DNA synthesis, inhibition of topoisomerase, prevention of cell proliferation, mitochondrial rupture/depolariza-tion, and induction of bacterial apoptosis.

EpiberberineEpiberberine, with the molecular formula of C20H18NO4, is a natural protoberberine from the C. rhizome. Epiberberine has many pharmacological functions, including antibacterial, anti-adipogenic, anticancer, antidyslipidemia activities, and so on (Liu et al., 2020).

The urease inhibitory activities of five alkaloids in C. rhi-zome, including berberine, coptisine, epiberberine, palmatine, and jateorhizine, were investigated by comparing the half maximal inhibitory concentration (IC50) values (Tan et al., 2017). The re-sults showed that the inhibition against urease was concentration-dependent inactivation, and epiberberine was the strongest inhibitor, which was even more effective than the standard urease inhibitor, acetohydroxamic acid. According to their inhibitory ability, the five alkaloids ranked as follows: epiberberine, palmatine, coptisine, jateorhizine, berberine. The H. pylori urease inhibition induced by epiberberine was slow-binding and uncompetitive. Furthermore, the active site sulfhydryl group of ureases played an important role in inhibiting progress and the inhibition was reversible. Molecular docking studies further investigated the binding mode between epiberberine and urease, 9-O-CH2 and 2-O-CH3 of epiberberine formed strong N–H≡O hydrogen bond to the backbone with the backbone H atom of Met-366 and Asn-168, respectively.

Besides those above, jatrorrhizine, as one of the alkaloids, also proved to have antibacterial activities. Yu et al. (2019) performed a checkerboard microdilution assay and used a murine thigh infec-tion model to investigate the synergistic effect of jatrorrhizine and norfloxacin against MRSA for in vitro and in vivo assays, respect-ively. The MIC of jatrorrhizine against MRSA was 64 mg/L. A syn-ergistic effect was achieved between jatrorrhizine and norfloxacin with fractional inhibitory concentration index (FICI) of 0.375. A re-verse transcription semiquantitative polymerase chain reaction and a molecular docking study were conducted to explain the synergistic effects. It was indicated that jatrorrhizine could suppress the expres-sion of bacterial drug efflux NorA, and could bind to NorA through hydrogen bonds, and hydrophobic and electrostatic interactions.

In comparison with berberine, there are relatively fewer studies about the antibacterial activities of coptisine, palmatine, epiberberine, and jatrorrhizine. Microcalorimetry was used to in-vestigate the antibacterial activities of these four alkaloids from C. rhizome (Feng et al., 2011). According to the results of Fan et al. (2008), the four alkaloids all showed significant antibacterial effects against S. aureus. As reflected in the power–time curves of S. aureus growth in the presence of each alkaloid, the time of the lag phase of bacteria growth (tp) was prolonged, and the maximum heat output (Pmax) decreased after treatment, which indicated that all four alkal-oids could inhibit the growth of S. aureus. Moreover, the antibac-terial effects of coptisine, palmatine, and jatrorrhizine against E. coli (Yan et al., 2008, 2009; Kong et al., 2009) and Bacillus shigae (B. shigae) (Yan et al., 2009) were also proved by microcalorimetry.

IntercomparisonAs summarized above, C. rhizome alkaloids have been widely proved to exert significant antibacterial activities against common gastrointestinal pathogens. The ability of antibacterial activities of alkaloids against pathogens, such as S. aureus (Fan et al., 2008), E. coli (Yan et al., 2008, 2009; Kong et al., 2009), and B. shigae (Yan et al., 2009), was investigated by comparing calorimetric data from power–time curves obtained by microcalorimetry. The order of their antibacterial activities was berberine>coptisine>palmatine>


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epiberberine>jatrorrhizine. However, the order of alkaloids against MRSA obtained by broth microdilution method was berberine>coptisine>jatrorrhizine>palmatine>epiberberine, which was different from the above results (Luo et al., 2013). Besides, the sequence of antimicrobial activities of alkaloids against Bifidobacterium adolescentis was also studied by microcalorimetry, and the result was palmatine>coptisine>berberine (Luo et al., 2013).

In conclusion, the different antibacterial effects of alkaloids against bacteria were attributed to various alkaloid structures. According to the research results, the functional groups methylenedioxy and methoxyl at C–2 and C–3 on the phenol ring might be the major group contributed to the activities of alkaloids, and methylenedioxy at C–2 and C–3 on the phenyl ring improved antibacterial activ-ities more remarkably than methoxyl (Yan et al., 2008, 2009; Kong et al., 2009). Besides, when the compounds bear the same func-tional group at C–2 and C–3, a methoxy at C–9 and C–10 showed higher activity than methylenedioxy (Kong et al., 2009). However, according to the results of Kong et al. (2009), substituent groups at C–9 and C–10 on the phenyl ring did not affect the antibacterial activities. Additionally, a synergetic effect against MRSA was found between berberine and epiberberine, jatrorrhizine and palmatine, jatrorrhizine and coptisine, but an antagonistic effect against MRSA was found between coptisine and epiberberine (Luo et al., 2013). The optimal combination of five alkaloids was berberine: coptisine: jatrorrhizine:palmatine:epiberberine=0.702:0.863:1:0.491:0.526, which exerted significant antibacterial activities in the inhibition of MRSA infected mouse model (Luo et al., 2013).

Dosage and toxicityThe bioactivity of berberine alkaloids by oral administration was very low, and the plasma concentration of alkaloids displayed an explicit nonliner relationship with oral dosage (Feng et al., 2015; Wu et al., 2019). As summarized by Wu et al. (2019), a daily single dose of coptisine was 1.5–40 g, and the doses of in vitro and in vivo for coptisine were in the range of 0.06–468 μmol/L and 0.0025–150 mg/kg, respectively.

The median lethal dosage (LD50) values of berberine by intra-venous injection, intraperitoneal injection and intragastric oral administration in mice were 9.0386, 57.6103 mg/mg and none, re-spectively (Kheir et al., 2010). According to Ma et al. (2010), the LD50 of the total extract of C. rhizome was 2.95 g/kg in mice, and they concluded that all alkaloids showed dose- and time-dependent cytotoxicity. In the acute toxicity study, LD50 of fibrous roots of C. rhizome was greater than 7000 mg/kg body weight in Kunming mice. Besides, 1.88 g/kg body weight of fibrous roots of C. rhizome did not produce obvious side effects in Sprague–Dawley rats, while 3.76 g/kg of body weight resulted in damage to liver and lung (Ning et al., 2015). The LD50 values of berberine, coptisine, palmatine, and epiberberine were 713.57, 852.12, 1533.68, and 1360 mg/kg in mice, respectively, and no mortality or morbidity were observed in the subchronic toxicity study (Yi et al., 2013).

In 1978, C. rhizome was implicated in causing neonatal jaundice and kernicterus in neonates suffering from glucose-6-phosphate de-hydrogenase (G6PD) deficiency, leading to the banning of C. rhi-zome and berberine in Singapore. Later, after accumulating studies pointing to the safety of C. rhizome for the general public and better understanding of G6PD deficiency, the Health Sciences Authority in Singapore reviewed and lifted the prohibition of C. rhizome and berberine (Ho et al., 2014). There was no organ toxicity or elec-trolyte imbalance in 20 patients where C. rhizome was adminis-tered for 1055 patient-days (Linn et al., 2012). No mortality or

remarkable clinical signs were seen and no adverse effects were found on rats administered with C. rhizome during the study (Lee et al., 2014).

ConclusionIt is well known that five isoquinoline alkaloids in C. rhizome, ber-berine, coptisine, palmatine, epiberberine, and jatrorrhizine, are the main contributors to its activities and functions. Among them, berberine is the most studied and possessed the best antibacterial activity. In addition, different alkaloids exert diverse antibacterial effects against pathogens, which may be attributed to the various substituent groups on the phenol ring of alkaloids. The alkaloids used in antibacterial experiments are commonly commercially pur-chased, which is different from dandelion, and this may ascribe to the difficulty of extraction and the low purity of extracts. Besides, microcalorimetry has been used as a mature method in investigating the antibacterial effects of alkaloids. To sum up, isoquinoline alkal-oids of C. rhizome have been proved to be potent in killing common bacteria and have potential application values in food and medicine.

Scutellaria baicalensisS. baicalensis is the member of the genus Lamiaceae, which are per-ennial plants and include about 350 species. It is also known as Huang-Qin in China and its roots are the main parts commonly used in TCM. Nowadays, the plants are widely cultivated in Shandong Province, Hebei Province, Shanxi Province, Gansu Province, and Inner Mongonia Autonomous Region of China (Wang et al., 2018).

More than 295 compounds have been isolated from S. baicalensis, including flavonoids, terpenoids, polysaccharides, and other com-pounds. Of those, baicalin, baicalein, wogonin, and oroxylin A were the main active compositions (Li et al., 2004; Shang et al., 2010; Lu et al., 2011). High-performance liquid chromatography (HPLC), thin-layer chromatography, mass spectrometry (MS), GC-MS, and capillary electrophoresis are usually applied to study these chemical compounds (Li et al., 2004).

In China, S. baicalensis has a medicinal history of at least 2000 years, and was used to treat various clinical diseases. Studies on its pharmacological effects showed that S. baicalensis possessed anticancer activities (Bie et al., 2017), antibacterial and antivirus ef-fects (Yang et al., 2005; Shi et al., 2016; Zhi et al., 2019), anti-inflam-matory activities (Feng et al., 2014; Kim et al., 2014), antidiabetic functions (Shin et al., 2020), and the ability to maintain bile acid homeostasis (Han et al., 2017).

Antibacterial activity of S. baicalensisThe antibacterial activities are mainly attributed to the presences of baicalein, baicalin, and volatile oil of S. baicalensis. A summary is presented in Table 3, and the profile of the antibacterial activities is shown in Figure 4.

BaicaleinIt was reported that l-lactic acid, as a substrate recognized and util-ized by H. pylori, was able to promote the growth and colonization of H. pylori (Takahashi et al., 2007). Thus, a newly developed fluoro-metric assay was developed by Takahashi et al. (2007) to screen the substances that had an inhibitory effect on l-lactic acid-dependent H. pylori. Baicalein was proved to significantly inhibit the growth of l-lactic acid-dependent H. pylori, which was probably achieved by influencing the l-lactic acid metabolic pathways of H. pylori. In a similar research (Chen et al., 2018), a lower concentration of baicalein

14 K. Chen et al.

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Tab

le 3

. S

um

mar

y o

f an

tib

acte

rial

act

ivit

ies

of

S. b

aica

len

sis

Phyt

oche

mic

al

com

poun

dSo

urce

Ant

ibac

teri

al r

esul

tR

elat

ed m

echa

nism

Ref

eren

ce

Bai

cale

inB

aica

lein

was

pur

chas

ed

com

mer

cial

lyl-

Lac

tic

acid

-dep

ende

nt a

nd c

lari

thro

myc

in-s

ensi

tive

H

. pyl

ori (

IC50

, 0.5

μm

ol/L

) l-

Lac

tic

acid

-dep

ende

nt a

nd c

lari

thro

myc

in-r

esis

tant

H

. pyl

ori (

IC50

, 1.1

μm

ol/L

)

Bai

cale

in c

ould

influ

ence

the

l-l

acti

c ac

id m

etab

olic

pat

h-w

ay o

f H

. pyl

ori

Mat

sum

oto

et a

l. (2

008)

Bai

cale

in w

as p

urch

ased

co

mm

erci

ally

H. p

ylor

i (1

6 μ

mol

/L a

nd 3

1.25

μm

ol/L

)B

aica

lein

cou

ld in

hibi

t th

e gr

owth

of

H. p

ylor

i, su

ppre

ss

the

expr

essi

on o

f va

cA g

enes

, and

dec

reas

e th

e ad

hesi

on

abili

ties

Che

n et

al.

(201

8)

Bai

cale

in w

as p

urch

ased

co

mm

erci

ally

Cip

roflo

xaci

n-re

sist

ant

MR

SA (

MIC

, 64–

256

μg/

mL

)

Cip

roflo

xaci

n-su

scep

tibl

e M

RSA

(M

IC, 3

2–64

μg/

mL

)

Cip

roflo

xaci

n-re

sist

ant

MR

SA (

FIC

I, 0.

38–1

.0, b

aica

lein

co

mbi

ned

wit

h ci

profl

oxac

in)

Bai

cale

in c

ould

res

tore

the

ant

ibac

teri

al a

ctiv

ity

by

inhi

biti

ng t

he N

orA

effl

ux p

ump

and

inhi

biti

ng t

he p

yru-

vate

kin

ase

of M

RSA

to

redu

ce t

he a

mou

nt o

f AT

P

Cha

n et

al.

(201

1)

Bai

cale

in w

as p

urch

ased

co

mm

erci

ally

P. a

erug

inos

a

Inhi

bit

the

form

atio

n of

bio

film

, 20

μm

ol/L

; pr

oteo

lysi

s of

Tra

R p

rote

in, 4

–40

mm

ol/L

Bai

cale

in c

ould

inhi

bit

QS

syst

em-r

elat

ed g

enes

Zen

g et

al.

(200

8)

Bai

cale

in w

as p

urch

ased

co

mm

erci

ally

P. a

erug

inos

a PA

O1

(MIC

, >10

24 μ

g/m

L)

Bai

cale

in c

ould

dow

nreg

ulat

e th

e tr

ansc

ript

ion

of Q

S-

regu

late

d ge

nes

and

tran

slat

ion

of Q

S-si

gnal

ing

mol

ecul

esL

uo e

t al

. (20

16)

Bai

cale

in w

as p

urch

ased

co

mm

erci

ally

S. a

ureu

s (a

ntib

iofil

m, 3

2 μ

g/m

L)

Bai

cale

in c

ould

inhi

bit

the

form

atio

n of

bio

film

and

sup

-pr

ess

the

expr

essi

on o

f Q

S-re

late

d ge

nes

Che

n et

al.

(201

6)

Bai

cale

in w

as p

urch

ased

co

mm

erci

ally

Clin

ical

pen

icill

inas

e-pr

oduc

ing

S. a

ureu

s (F

ICI,

0.14

–0.3

8,

baic

alei

n co

mbi

ned

wit

h pe

nici

llin

G/a

mox

icill

in)

Bai

cale

in c

ould

inhi

bit

the

acti

vity

of

peni

cilli

nase

Qia

n et

al.

(201

5)

Bai

cale

in w

as p

urch

ased

co

mm

erci

ally

S. a

ureu

s N

ewm

an s

trai

n an

d S.

aur

eus

AT

CC

292

13 s

trai

n I

(MIC

, gre

ater

tha

n 10

24 μ

g/m

L)

Bai

cale

in d

id n

ot s

igni

fican

tly

inhi

bit

the

grow

th o

f S.

aur

-eu

s, b

ut a

tten

uate

d th

e vi

rule

nce

of S

. aur

eus

by b

lock

ing

the

coag

ulas

e of

van

Will

ebra

nd f

acto

r-bi

ndin

g pr

otei

n

Zha

ng e

t al

. (20

20)

Bai

cale

in w

as p

urch

ased

co

mm

erci

ally

S. t

yphi

mur

ium

A

hig

h-th

roug

hput

ass

ayB

aica

lein

cou

ld t

arge

t S.

typ

him

uriu

m p

atho

geni

city

isla

nd 1

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mon

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(16 μmol/L) could suppress the expression of the vacA genes (a major virulent factor of H. pylori) and inhibit the growth of H. pylori, and 31.25 μmol/L of baicalein could decrease the adhesion abilities of H. pylori to human gastric adenocarcinoma (AGS) cells. According to a high-throughput assay conducted by Tsou et al. (2016), baicalein could act on S. typhimurium pathogenicity island 1 (SPI-1) type III secretion system (T3SS) effectors and translocases, which was the key virulence pathway of bacteria, to inhibit the bacterial invasion of epi-thelial cells. Zeng et al. (2008) performed an automated docking pro-gram to search for quorum sensing (QS) inhibitors of P. aeruginosa. The results indicated that although baicalein did not exert antibac-terial effects against P. aeruginosa, it significantly inhibited biofilm formation at 20 μmol/L and promoted proteolysis of the signal re-ceptor TraR protein at 4–40 mmol/L, which manifested the inhib-ition activities of baicalein on QS system. However, in another study, the MIC of baicalein against P. aeruginosa was over 1024 μg/mL (Luo et al., 2016), and the sub-MIC concentration of baicalein could decrease the expression of QS-regulated virulence genes, including genes related to motility and biofilm formation. Moreover, Chen et al. (2016) proved that 32 μg of baicalein significantly exhibited antibiofilm effects against S. aureus in vitro, and decreased the gene expressions of agrA, sarA, and ica in QS system. Baicalein could at-tenuate the virulence of S. aureus by blocking the coagulase of van Willebrand factor-binding protein (vWbp), which was one of the key virulence factors, but did not significantly inhibit the growth of S. aureus. Thermal shift and fluorescence quenching assays, molecular dynamics simulations, and mutagenesis assays proved that baicalein could directly bind to vWbp through the Asp-75 and Lys-80 residues (Zhang et al., 2020).

A synergistic effect was found between baicalein and ciprofloxacin against 12 of 20 clinical ciprofloxacin-resistant MRSA, and an additive effect was observed against ciprofloxacin-susceptible MRSA by the checkerboard dilution test and time–kill assay. Baicalein could restore the antibacterial activities of ciprofloxacin against MRSA, possibly by inhibiting the NorA efflux pump. Besides, the specific pyruvate kinase

of MRSA inhibited by baicalein could lead to the deficiency of adeno-sine triphosphate (ATP; Chan et al., 2011). A synergetic activity was achieved against 20 clinical penicillinase-producing S. aureus when baicalein was combined with penicillin G/amoxicillin with FICI values ranging from 0.14 to 0.38, which could be ascribed to the inhibition of penicillinase activities by baicalein (Qian et al., 2015). According to the study of Peng et al. (2011), baicalein might inhibit the SOS-response in S. aureus induced by ciprofloxacin to decrease the anti-biotic resistance of S. aureus. Moreover, synergistic effects of baicalein and tetracycline against MRSA (Fujita et al., 2013), baicalein and cefotaxime against K. pneumonia (Cai et al., 2016), and baicalein and linezolid against MRSA (Liu et al., 2020) were also found.

BaicalinThe QS circuit was important in controlling virulence factors and bio-film formation of P. aeruginosa, and experiments proved that baicalin could inhibit virulence phenotypes (LasA protease, LasB elastase, pyocyanin, rhamnolipid, motilities, and exotoxin A), and QS-regulatory genes (lasl, lasR, rhll, rhlR, pqsR, and pqsA) to reduce the infection of P. aeruginosa (Luo et al., 2017). In another study (Peng et al., 2019), baicalin was proved to inhibit the QS of E. coli by suppressing the expression of virulence genes and inhibiting the formation of biofilm. In addition, baicalin could downregulate the expression of Toll-like re-ceptor (TLR2), and the phosphorylation of p53 in the mammary glands in S. aureus-induced mastitis (Guo et al., 2014). According to the study by Wang et al. (2018), baicalin was able to bind to the center of Sortase B (SrtB), a crucial virulence factor of S. aureus, to decrease S. aureus in-fections. The antagonistic activities against S. typhimurium of baicalin were also testified, and the MIC was >128 μg/mL, and transcription levels of Salmonella pathogenicity island 1 virulence-associated genes were significantly decreased by baicalin.

Furthermore, in the research of Zhou et al. (2016), baicalin was incorporated into silk to produce a hygiene-related and health tex-tile product, which had higher antibacterial effect against E. coli and S. aureus than baicalin itself.

Figure 4. The profile of antibacterial effects of Scutellaria baicalensis. QS, quorum sensing.

16 K. Chen et al.

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Volatile oilVolatile oil was firstly identified by Fukuhara et al. through GC-MS, and proved to exert significantly antibacterial activities against B. subtilis, Enterococcus faecalis, K. pneumoniae, and Salmonella enterica, with MIC values from 31.25 μg/mL to 125.0 μg/mL (Fukuhara et al., 1987; Pant et al., 2012). The principal contents of volatile oil included oxy-genated monoterpene hydrocarbons, linalool, and 1-octen-3-ol (Pant et al., 2012), which might be the active components. Except for these above, there are relatively fewer studies about the antibacterial activ-ities of volatile oil, and the single active components with antibac-terial activities need to be purified and further studied.

Dosage and toxicityThe aqueous extracts of S. baicalensis had no significant effects in body weight, clinical symptoms and mortality on rabbits and guinea pigs (Kim et al., 2013). According to the experiment of Yi et al. (2018), when male and female rats were fed the ethanol extract of S. baicalensis at a dose of 2500 mg/kg/d, the liver tissue showed some adverse reactions but returned to normal after withdrawal, and glucose, electrolyte, and lipid levels also showed some changes. In addition, no other functional or organic lesions were found during the treatment.

According to the summary of Zhao et al. (2019), although there was no obvious adverse reaction after intake of S. baicalensis, it was not suitable for people with spleen and stomach deficiency for its bitter and cold medicinal properties.

ConclusionBaicalein and baicalin are the main flavonoids for the antibac-terial effects of S. baicalensis. In the references above, baicalein and baicalin were almost obtained commercially. Their possible antibac-terial mechanisms included inhibiting bacterial growth, reducing bacterial virulence, destroying the formation of bacterial biofilm, and decreasing bacterial adhesion abilities. Among them, QS-related virulence factors are one of the most important sites of action. It is noteworthy that baicalein and baicalin were also significantly effective in restoring the antibacterial activities of traditional anti-biotics against resistant bacteria and could work well with trad-itional antibiotics to kill pathogenic bacteria. Baicalein or baicalin seems to be a promising novel effective synergistic antibacterial agent to solve the problems of antibiotic resistance. However, other antibacterial mechanisms still need to be further exploited.

Conclusion and Outlook

According to the above statements, these three Chinese traditional medicines all bear significant antibacterial activity against common foodborne pathogens. The extracts by different solvents or from dif-ferent plant parts contain different kinds and concentrations of ac-tive compounds, which could lead to the differences in antibacterial effects. Different antibacterial activity of extracts is reflected in two aspects, including different antibacterial spectra to different bacteria and different level of antibacterial activity to the same strain of bac-terium. The components of the extracts from these three plants re-viewed here were different, and thus exerted different antibacterial effects. As for the involved antibacterial mechanisms of the extracts from these three plants, it was preliminarily proved that the sites of actions were usually the cell membrane, cell wall, nucleic acids, or some metabolic pathways of bacteria, which still need to be further studied.

TCM, as an important natural source with a long history, is a unique medicine in traditional Chinese treatment. In the era of widespread antibiotic resistance, the discovery of new, natural, safe, and effective antibacterial compounds opens a new area for solving foodborne illness and overcoming antibiotic resistance. Thus, ex-ploring natural materials from medicinal herbs has inspired a new wave for the discovery of alternative and green antibacterial drugs. In long-term research, although the potential of some natural prod-ucts for bacteriostasis extracted from medicinal plants has been proved, the challenge of discovering new substances is still huge. For example, the efficiency of extracting medicinal plants is low, it is very difficult to obtain pure substances, and it is hard to identify the extracted unknown compounds. More attention and research are urgently needed to explore the antibacterial mechanisms of these natural compounds, which will pave the way for seeking effective natural drugs or food additives. Thus, on the one hand, it is crucial to purify the active substances to investigate the antibacterial ac-tivity and clarify the antibacterial mechanisms. On the other hand, advances in the field of natural products used for solving antibiotic resistance need multidisciplinarity and the combination of various technologies.

On account of the excellent advantages of these plants used as antibacterial agents, undoubtedly, they will be a good substitute or adjuvant of antibiotics. However, before this, further endeavor is still needed in the following aspects of exploiting abundant plants with outstanding antibacterial activities, determining the structures and properties of natural products, and more importantly, clearly clari-fying the deeper antibacterial mechanisms.

Author ContributionsZhaojie Li and Kun Chen: Conceptualization and methodology and valid-ation; Kun Chen, Xiudan Hou, and Wei Wu: Investigation; Zhaojie Li, Wei Wu, and Kun Chen: Writing original draft; Qingli Yang: Writing, review and editing, and supervision; Xiudan Hou and Wei Wu: Project administration; Zhaojie Li and Qingli Yang: Funding acquisition. All authors have read and agreed to the published version of the manuscript.

FundingThis work was supported by the National Science Foundation of Shandong Province (No. ZR2020MC217), the Breeding Plan of Shandong Provincial Qingchuang Research Team (No. 2019-135), China.

Conflict of InterestThe authors declare no conflict of interest.

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A review: antimicrobial properties of several medicinal plants ...

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