A Review: Antimicrobial Properties of Several Medicinal Plants Widely Used in Traditional Chinese Medicine

Food Quality and Safety, 2021, 5, 1–22
https://doi.org/10.1093/fqsafe/fyab020
Review
Review
A review: antimicrobial properties of several

medicinal plants widely used in Traditional
Downloaded from https://academic.oup.com/fqs/article/doi/10.1093/fqsafe/fyab020/6364206 by guest on 30 November 2021

Chinese Medicine
Kun 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: rice407@163.com; Zhaojie Li, College of Food Science and Engineering, Qingdao Agricultural University, Qing-
dao 266109, China. E-mail: hunterlee_81@163.com
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 coli (E. coli), Listeria monocytogenes (L. monocytogenes), Salmonella

typhimurium (S. typhimurium), Staphylococcus aureus (S. aureus),
Numerous infectious diseases, such as inflammatory bowel disease,
irritable bowel syndrome, and colorectal cancer (Sell and Dolan, Shigella dysenteriae, Mycobacterium tuberculosis, Bacillus cereus (B.
2018), are caused by pathogenic bacteria each year worldwide, re- cereus), and Clostridium perfringens (Chen et al., 2017), which are
sulting in millions of deaths, and contributing significantly to the common foodborne pathogens. The discovery and development of
global burden of mortality (Jones et al., 2008). The majority of bac- antibiotics have contributed to the cure of infectious diseases, and
terial diseases are due to intoxication or infection with Escherichia significantly decreased the mortality rates of human around the
© The Author(s) 2021. Published by Oxford University Press on behalf of Zhejiang University Press.
1
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2 K. Chen et al.
world. Since their developments from the 1940s, antibiotics have be- berberine (Zhu et al., 2011; Sahibzada et al., 2018), allicin (Choo
come life-saving medicines that are integral to human health (Butler et al., 2020), antrographolide (Zhu et al., 2011; Wen et al., 2014),
and Paterson, 2020). AMPs (Benko-Iseppon et al., 2010; Nawrot et al., 2014), and so
However, the misuse or overuse of antibiotics has caused the on. These nonantibiotic drugs act in different manners on micro-
increasing antibiotic resistance (AR) of pathogenic bacteria, which bial growth. They may have direct antimicrobial activities (anti-
has become one of the greatest threats to public health (Chandra microbial nonantibiotics), increase the efficacy of an antibiotic when
et al., 2017). The AR abilities of microorganisms can escape the coadministered (helper compounds), or change the pathogenicity of
effects of the drugs designed to kill or inhibit them by different microorganisms or activity on the physiology, such as modulating
mechanisms, such as neutralizing the antibiotics, pumping them macrophage activities (Martins et al., 2008).
outside of the cell, or modifying their outer structure, resulting in In an era where it is becoming increasingly difficult to find new
reducing the effects of drugs to the bacteria (Silhavy et al., 2010). antibacterial drugs, it is very important to understand the antibac-

Consequently, the use of these antibiotics is becoming increasingly terial activities of these medicinal plants comprehensively. After
restricted because of their toxicity possessed by themselves as well searching in the literature, we found the most recent articles referring
as their trickish AR. Despite all the efforts that have been devoted to this topic. In this narrative review, we summarize the most im-
to combat AR on the national and international scale, this situation portant and widely used medicinal plants that were reported to have
is still on the rise. Based on the 2019 report from the Centers for antibacterial activities. A general literature search from 2010 to 2020
Disease Control and Prevention in the USA (Doînel et al., 1978), was conducted using different databases including Science Direct,
more than 2.8 million antibiotic-resistant infections occurred each Web of Science, and PubMed. According to the literature, three me-
year, and as a result, more than 35,000 people died. Therefore, there dicinal plants with antibacterial activities, Taraxacum officinale (T.
is an urgent and compelling need to develop new and effective anti- officinale), Coptis rhizome (C. rhizome), and Scutellaria baicalensis
bacterial compounds with novel modes of action or as alternatives (S. baicalensis), were screened and reviewed by prioritization. The
to antibiotics to address these serious problems. In early 2017, the antibacterial properties of each plant were detailed, including the
World Health Organization (WHO) convened a group of experts extraction methods, antibacterial activities of different parts of the
that used a multicriteria decision analysis method to prioritize the plant or the plant-derived compounds, spectra of antibacterial ac-
need for new drugs to treat antibiotic-resistant bacteria (Tacconelli tivities, toxicity, and so on. In addition, the possible mechanisms of
et al., 2018). action for the antibacterial activities of some of the extracts from the
Several strategies have been reported to fight and control bac- medicinal plants were described to a certain degree. The problems
terial AR, such as the development of new antimicrobial or auxiliary needing further study and prospects are discussed in this review.
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., Search Strategy and Data Extraction
2018; Breijyeh et al., 2020), the synthesis of novel nanomaterials According to the number of the publications about the plants with
(Manukumar et al., 2017), and the study of novel targets that re- antibacterial activities during 2010–2020 (Figure 1), three plants
sistant bacteria are sensitive to (Chen et al., 2017; Qin et al., 2020). were selected to detail in our review, i.e., T. officinale, C. rhizome,
Another promising trend is by referring to nature to develop natur- and S. baicalensis, which have obtained the most attention and are
ally derived agents with antibacterial activities. also widely applied in Traditional Chinese Medicine (TCM) or food.
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- Medicinal Plants With Antibacterial Activities
ical diversity (Amedei and Niccolai, 2014). Ethnopharmacology, a Taraxacum officinale
multidisciplinary study of indigenous remedies, has great significance Plants of the genus Taraxacum, which are members of the family
in the discovery of new drugs from natural sources (Holmstedt and Asteraceae and are widely distributed in the warmer temperate zones
Bruhn, 1983). The use of ‘medicinal plants’ has become a hotspot of the northern hemisphere, are perennial herbs and inhabit waste-
target of scientific research, because they are rich in active metab- lands, roadsides, and courtyards (Schütz et al., 2006a). According
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 Perilla frutescens 241
in which one or more of their organs contain substances that can be Wolfiporia extensa 114
used for therapeutic purposes or may be used as precursors in the Fallopia japonica
Medicinal plants
165
synthesis of other drugs. More valuable, some of these medicinal Angelica dahurica 155
plants are also economic vegetables, such as Solanaceae (Silalahi Forsythia suspensa 126
et al., 2014), dandelion (Astafieva et al., 2012), etc. They are as- Fructus mume 94
sociated with advantages such as lower toxicity, economical, and Prunus mume 178
multiple targets (Lin et al., 2016; Ma et al., 2019). It is well known Scutellaria baicalensis 966
that plants can develop different constitutive and inducible mechan- Taraxacum officinale 472
isms for the protection from pathogenic infection via morphological Coptis rhizome 278
barriers, secondary metabolites, or antimicrobial peptides (AMPs; 0 200 400 600 800 1000 1200
Benko-Iseppon et al., 2010). There are some natural medicinal com- Amount of articles
pounds referred to as nonantibiotics from medicinal plants, which
possess moderate to powerful antibacterial activities (Yuan et al., Figure 1. The number of publications about medicinal plants with
2016), such as essential oils (Avonto et al., 2013; Lee et al., 2017), antibacterial activities
Antimicrobial properties of several plants widely used in TCM 3
to Kirschner et al. (2015), the genus includes about 60 sections MIC of 1600 μg/mL, which was consistent with the study results
with about 2800 species. Among all the species, T. officinale, of Ghaima et al. (2013). The main components of the extracts were
Taraxacum mongolicum (T. mongolicum), Taraxacum laevigatum, identified by nuclear magnetic resonance (NMR) and gas chroma-
Taraxacum kok-saghyz, and Taraxacum platycarpum are common tography–mass spectrometry (GC-MS). The hexane extracts mainly
kinds. In particular, T. officinale, known as the dandelion (Martinez included lupeol acetate, betulin, lupeol, and 3,7,11,15-tetramethyl-
et al., 2015), is the most widely studied and used. 2-hexadecen-1-ol, while the ethyl acetate extracts did not have
Dandelion has been extensively used as a phytomedicine for its lupeol. It was concluded by Díaz and colleagues that the presences
curative properties, and is included in the 2015 edition of the Chinese of phenolic compounds, flavonoids, tannins, terpenes, alkaloids, and
Pharmacopoeia (Liang et al., 2020). A large number of studies have proteins in the extracts imparted the antibacterial property of dan-
demonstrated that dandelion has many pharmacological effects such delion, which may act on the bacterial membrane (Díaz et al., 2018).
as diuretic (Clare et al., 2009), antioxidant (Jędrejek et al., 2017; To study the metabolite profile of dandelion, the authors employed

Jędrejek et al., 2019), antibacterial (Sengul et al., 2009; Sharifi- N-hexane to separate the nonpolar constituents in dandelion leaves
Rad et al., 2018), anti-inflammatory (Jeon et al., 2008; Hu et al., and a methanol:water (6:4) solution to distill the polar compositions
2017), anticancer (Ovadje et al., 2016), hypoglycemic (Choi et al., of dandelion leaves; the extracts were then also analyzed by NMR
2018), hepatoprotective (Davaatseren et al., 2013; Cai et al., 2017), and GC-MS (Grauso et al., 2019). The obtained results indicated
immune-enhancing (Lee et al., 2012; Tan et al., 2018), and so on. that malic acid, malonic acid, myo-inositol, caffeoyl derivatives, and
As we know, these functions are bound up with its constituents. It is flavonoids were the specific polar materials with a high content ex-
reported that dandelion contains many active ingredients including isting in the extract; besides, nonpolar ingredients were mainly com-
sesquiterpene lactones (Kisiel and Barszcz, 2000; Jędrejek et al., posed of saturated fatty acid, such as palmitic acid, oleic acid, and
2019), phenolic acids (Budzianowski, 1997; Kisiel and Barszcz, stearic acid.
2000; Schütz et al., 2005), flavonoids (Kristó et al., 2002; Schütz The antibacterial effects of methanol, chloroform, and water ex-
et al., 2005), triterpenes (Akashi et al., 1994; Akihisa et al., 1996), tracts of dandelion leaves were also investigated. Sohail et al. (2014)
coumarins (Budzianowski, 1997), polysaccharides (Cai et al., 2019; utilized the agar well diffusion method to determine the inhibition
Guo et al., 2019; Wang et al., 2019), inulin (Schütz et al., 2006b), zone diameter (IZD) of the extracts against four species of bacteria,
and sterols (Ivanov et al., 2018), which may contribute to these E. coli, Bacillus subtilis (B. subtilis), S. aureus, and Pseudomonas
pharmacological effects. Among those, the characteristic of antibac- aeruginosa (P. aeruginosa). The methanol extracts showed the
terial activity is one of the most important pharmacological effects. highest antibacterial activities against S. aureus (13 mm), and
Interestingly, it is reported that the extracts from different parts of chloroform extracts significantly inhibited E. coli (14 mm), while the
the dandelion exert various pharmacological effects including anti- water extracts had no activity against all test bacteria. It was found
bacterial activity, which is due to the existence of different active that all three extracts exerted no antibacterial effects on the Gram-
ingredients in these extracts. 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-
Antibacterial activities of dandelion teria. For example, the same conclusions were obtained by Ghaima
It is true that extracts from different solvents possess different anti- et al. (2013), who found that the ethyl acetate extracts of dandelion
bacterial activities, which are reflected in two aspects, namely, dif- leaves gave a large IZD in B. cereus (18 mm), but showed poor anti-
ferent antibacterial spectra to different bacteria and different levels bacterial effects against E. coli and Salmonella typhi (S. typhi). The
of antibacterial activity to the same bacterium. This makes sense outer membrane of the Gram-negative bacterial cell wall, which acts
because extracts from different solvents contain different active in- as a barrier to many substances including antibiotics, contributes to
gredients. According to current reports, the common solvents used the high tolerance of Gram-negative bacteria (Nikaido, 1994; Gao
for extraction include hexane, ethyl acetate, methanol, chloroform, et al., 1999; Ghaima et al., 2013).
ethanol, and water, and even a combination of these solvents in ap- Additionally, many researchers used ethanol or water to extract
propriate proportions. The solvent extraction method is the most the dandelion leaves, and investigated the antibacterial activities of
common method for the extraction of active compounds. Hydrogen the extracts. Specifically, it was found that 100 mg/mL and 200 mg/mL
peroxide hydrolysis, ultrasonic-assisted extraction, and enzyme- ethanol extracts had great inhibition on the growth of E. coli and
assisted extraction are usually used to extract active polysaccharides S. aureus, and 50 mg/mL only inhibited E. coli (Adebayo and Issah,
from dandelion. 2012), which was consistent with the previous research (Simsarian
The antibacterial activity of different parts of dandelion are et al., 2011), while the water extracts were only active on E. coli at
detailed in this review. A summary of the antibacterial activity is 100 mg/mL and 200 mg/mL. However, Jassim et al. (2012) proved
presented in Table 1, and the profile of the antibacterial activity is that the alcohol extracts exhibited antibacterial activity against
shown in Figure 2. 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
Dandelion leaves and 200 mg/mL. The water extracts had the same results except
The hexane and ethyl acetate extracts were investigated for their for no inhibition on E. coli at 0.5 mg/mL, which was also different
antibacterial effects against several bacteria including E. coli, Proteus from the results of Adebayo and Issah (2012). However, in another
mirabilis (P. mirabilis), Klebsiella pneumoniae (K. pneumoniae) and similar experiment, the water extracts of dandelion leaves did not
S. aureus by broth serial dilution (Díaz et al., 2018). S. aureus was show antibacterial activity against many common bacteria (Woods-
significantly inhibited by hexane extract at 200 μg/mL and the Panzaru et al., 2009). Furthermore, a water solution of ethanol
minimum inhibitory concentration (MIC) values were 400 μg/mL (40 per cent) was used as extract solvent to evaluate the antibacterial
and 800 μg/mL for other bacteria, while ethyl acetate extracts only activity of dandelion leaves. It was shown that the extracts exhib-
exhibited low antibacterial activity against E. coli, showing an ited antibacterial activity against E. coli, while they had no effect on
4 K. Chen et al.
Table 1. Summary of antibacterial activities of dandelion extracts
Parts of Extract solvent Antibacterial activity Related mechanism Reference

dandelion
Roots Methanol (2 mg/mL) S. aureus (MIC, 500 μg/mL) NR Kenny et al. (2015)

MRSA (MIC, 500 μg/mL)
B. cereus (MIC, 500 μg/mL)
DCM S. mutans (IZD, 21.00 mm and 22.00 mm) NR Amin et al. (2016)
(0.5 mg/50 μL) S. pyogenes (IZD, 28.67 mm and 29.00 mm)
(1 mg/50 μL) S. pneumonia (IZD, nil and nil)
S. aureus (IZD, 24.00 mm and 26.33 mm)
P. aeruginosa (IZD, nil and nil)

Ethyl acetate S. mutans (IZD, 18.00 mm and 20.33 mm)
(1 mg/50 μL) S. pneumonia (IZD, 21.75 mm and 22.67 mm)
Methanol S. mutans (IZD, 15.67 mm and 16.67 mm)
Aqueous S. mutans (IZD, 16.33 mm and 18.00 mm)
(0.5 mg/50 μL) S. pyogenes (IZD, 20.00 mm and 21.00mm)
Water S. aureus (MIC, nil) NR Kenny et al. (2014)
(2 mg/mL) MRSA (MIC, nil)
B. cereus (MIC, nil)
E. coli (MIC, nil)
S. typhi (MIC, nil)
Ethanol S. aureus (MIC, 375 μg/mL)
(2 mg/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) NR Díaz et al. (2018)
S. aureus (MIC, 200 μg/mL)
K. pneumoniae (MIC, 400 μg/mL)
P. mirabilis (MIC, 800 μg/mL)
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) Secondary metabolites Sohail et al. (2014)
S. aureus (IZD, 13.0 mm) like alkaloids, tannins,
E. coli (IZD, 10.0 mm) and flavonoids might
P. aeruginosa (IZD, 3.0 mm) be responsible for anti-
Chloroform B. subtilis (IZD, 5.0 mm) bacterial activity
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 E. coli (IZD, 23.50 mm, 16.00 mm, 10.50 mm) NR Adebayo and Issah
(200 mg/mL) S. aureus (IZD, 10.75 mm, 9.00 mm, nil) (2012)
(100 mg/mL) K. pneumonia (IZD, nil, nil, nil)
(50 mg/mL) P. aeruginosa (IZD, nil, nil, nil)
Aqueous E. coli (IZD, 7.50 mm, 5.25 mm, nil)
(200 mg/mL) S. aureus (IZD, nil, nil, nil)
(100 mg/mL) K. pneumonia (IZD, nil, nil, nil)
(50 mg/mL) P. aeruginosa (IZD, nil, nil, nil)
Table 1. Continued

dandelion
Alcoholic S. aureus (IZD, nil, 4–10 mm, 4–10 mm) The leaf extracts had an Jassim et al. (2012)
(0.1 mg/mL) P. mirabilis (IZD, nil, 1–4 mm, 1–4 mm) active effect on the bac-
(0.5 mg/mL) E. coli (IZD, nil, 1–4 mm, 1–4 mm) terial cell membrane, and
(1 mg/mL) the inhibitory effects might
Water S. aureus (IZD, nil, 4–10 mm, 4–10 mm) be due to the presence of
(0.1 mg/mL) P. mirabilis (IZD, nil, 1–4 mm, 1–4 mm) glycosides, phenolic com-
(0.5 mg/mL) E. coli (IZD, nil, nil, 1–4 mm) pounds, tannins, flavon-
(1 mg/mL) oids, alkaloids, proteins

Ethyl acetate S. typhi (IZD, 14 mm) NR Ghaima et al.
S. aureus (IZD, 16 mm) (2013)
B. cereus (IZD, 18 mm)
E. coli (IZD, 16 mm)
Methanol:water B. cereus (MIC, 0.037 mg/mL, 0.20 mg/mL) NR Petropoulos et al.
80:20 v/v S. aureus (MIC, 0.30 mg/mL, 0.90 mg/mL) (2019)
(1st growing period L. monocytogenes (MIC, 0.30 mg/mL, 0.90 mg/mL)
of dandelion) E. coli (MIC, 0.15 mg/mL, 0.30 mg/mL)
(2nd growing period S. typhimurium (MIC, 0.15 mg/mL, 0.60 mg/mL)
of dandelion)
Flowers DCM S. mutans (IZD, 16.33 mm and 18.00 mm) NR Amin et al. (2016)
(0.5 mg/50 μL) S. pyogenes (IZD, 20.33 mm and 21.33mm)
Novel antibacterial P. syringae (IZD, 7 mm, 8 mm, 7 mm) NR Astafieva et al.
peptides B. subtilis (IZD, 5 mm, 3 mm, 3 mm) (2012)
(ToAMP1)
(ToAMP2)
(ToAMP3)
Stems DCM S. mutans (IZD, 14.00 mm and 16.00 mm) NR Amin et al. (2016)
6 K. Chen et al.
Table 1. Continued

dandelion
Whole Hydrogen peroxide B. subtilis (IZD, 12.04 mm) Dandelion-derived Qian et al. (2014)
plants S. aureus (IZD, 16.15 mm) polysaccharides played
E. coli (IZD, 13.21 mm) the function
Cellulase-assisted B. subtilis (IZD, 11.02 mm) Dandelion-derived Wang (2014)
extraction S. aureus (IZD, 15.26 mm) polysaccharides played
E. coli (IZD, 12.47 mm) the function
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.
Figure 2. The profile of antibacterial activities of Taraxacum officinale
S. aureus (Ionescu et al., 2013). In order to dissect the material base other related reports, alpha-tocopherols were reported to destroy the
of the antibacterial action, the phytochemical constituents of the efflux pumps of S. aureus to reduce resistance (Tintino et al., 2016),
ethanol or water extracts of dandelion leaves were screened in these and organic acids were able to make the bacterial growth environment
two researches above. In the study of Adebayo and Issah (2012), more acidic, and inhibit the formation of capsular polysaccharide of
the extracts by ethanol and water did not contain flavonoids, which bacteria to exert antibacterial effects (Chen et al., 2011; Lin et al.,
were detected in the extracts by ethanol in the study of Jassim et al. 2013; Mitani et al., 2018). Therefore, it is understandable that ex-
(2012). The same situation occurred with saponins. tracts from the same parts of dandelion by different solvents exhibit
It is well acknowledged that the biological functions of medicinal different antibacterial spectra, because they contain different active
plants are bound up with their constituents, which is same for dande- ingredients. Surprisingly, those researches show that extracts from the
lion and its antibacterial activity. It was reported that plant secondary same parts exert different antibacterial spectra or a different degree of
metabolites, such as tannins, steroids, saponins, phenolic compounds, antibacterial activity to the same bacterium. The different extraction
flavonoids, terpenes, alkaloids, glycosides, and peptides, play an im- procedures and parameters or the bioassays performed may result in
portant role in antibacterial activity (Nweze et al., 2004; Astafieva this disaccord.
et al., 2012; Díaz et al., 2018). These bioactive compounds show anti- The antibacterial activities of two growing periods of dande-
bacterial effects through different mechanisms. For example, saponins lion (samples were collected on 17 October 2015 and 17 January
have been reported to play a part in managing inflammation (Adebayo 2016, respectively) against E. coli, L. monocytogenes, B. cereus,
and Issah, 2012); tannins work by reacting with proteins has been S. aureus, and S. typhimurium were carried out by the microdilution
proved to provide a tanning effect necessary for treating inflammation method, and dandelion was extracted by methanol:water (80:20
and inhibiting carrier enzymes and proteins in cell membranes (Kass v/v; Petropoulos et al., 2019). Meanwhile, phenolic compounds,
and Seastone, 1944; Parekh and Chanda, 2007); alkaloids are able to tocopherols, and organic acids of extracts were tested. The results
interact with the DNA, and the phenolic compounds formed complex indicated that the extracts from the two growing periods both sig-
with dissolved protein out of the cells or with cell membranes to kill nificantly inhibited the growth of selected bacteria, and among
bacteria (Nikaido, 1994; Hu and Kitts, 2005; Jassim et al., 2012). In them, B. cereus was the most sensitive bacteria, in agreement with
the results of Ghaima et al. (2013), while the MIC values of the acid, narirutin, pyrogallol, quinic acid, and luteolin, which may con-
first growing period were lower than the second, and dandelion tribute to the antibacterial effects of dandelion. Sengul et al. (2009)
had a better antibacterial effect in the first growing period. The also ascribed the antibacterial effects of the methanol extracts to
composition analysis results showed that chicoric acids were the phenolics, which was related to its antioxidant activities. However,
most abundant phenolic compounds, γ- and δ-tocopherols were the study results of López-García et al. (2013) were contrary to the
the main tocopherols of dandelion, and oxalic acid was the amp- above conclusions. Although there were phenolic compounds in
lest organic acid. the aqueous methanol (90 per cent, v/v) of dandelion flowers, the
Except for direct use of dandelion leaf extracts for antibacterial growth of S. aureus and E. coli was not inhibited.
activities, the methanolic extracts of dandelion leaves are used as a
function of bio-inspired green synthesis for the fabrication of silver Dandelion flowers
nanoparticles (AgNPs; Rasheed et al., 2017). Due to small size and According to the research of Amin et al. (2016), dandelion flowers

large surface area characteristics of AgNPs, the generated AgNPs were firstly extracted by four extraction solvents (DCM, ethyl acetate,
presented better antibacterial activity against S. aureus and E. coli methanol, and water; 0.5 mg/50 μL and 1 mg/50 μL), and the antibac-
than the extract itself, which provides a promising strategy for terial properties of extracts against five bacteria (S. pyogenes, S. pneu-
solving antibiotic resistance of bacteria. monia, P. aeruginosa, S. aureus, and S. mutans) were carried out by the
agar well diffusion method. The methanol extracts had the maximum
Dandelion roots inhibition zone diameter against S. pyogenes (IZD, 26.33 mm and
The antibacterial efficacies of crude and dialyzed extracts from dan- 27.33 mm) and also exhibited antibacterial effects against S. mutans
delion roots by several solvents were examined against three Gram- and S. aureus, while the ethanol extracts of dandelion flowers did not
positive bacteria (S. aureus, methicillin-resistant Staphylococcus show any antibacterial effects against E. coli, S. aureus, P. aeruginosa,
aureus (MRSA), and B. cereus) and two Gram-negative bacteria and B. subtilis (Khan et al., 2011). Besides, according to Amin et al.
(E. coli and S. typhimurium; Kenny et al., 2015). The hexane ex- (2016), S. pyogenes and S. aureus were sensitive to the various extracts,
tracts exhibited antibacterial activities against B. cereus (MIC= while S. pneumonia and P. aeruginosa were resistive to all extracts.
1000 μg/mL), the dimethyl sulfoxide (DCM) extracts inhibited However, in another similar study (Qiao and Sun, 2014), the authors
S. aureus and MRSA (MICs=1000 μg/mL), and the methanol tested the antibacterial effects of ethanol extracts of T. mongolicum
hydrophobic extracts were active against all three Gram-positive flowers and its fractions (petroleum ether, ethyl acetate, and water
bacteria (MICs=500 μg/mL), while none of them showed inhib- fractions) against E. coli, B. subtilis, S. aureus, Proteus vulgaris, and
ition on Gram-negative bacteria; similar results were reported by P. aeruginosa. The ethanol and ethyl acetate extracts showed signifi-
Amin et al. (2016) and Kenny et al. (2014). According to the re- cant inhibition on the growth of both Gram-negative and Gram-
search of Amin et al. (2016), dandelion roots were extracted by four positive bacteria, especially B. subtilis and P. aeruginosa. On the other
solvents (DCM, ethyl acetate, methanol, and water; 0.5 mg/50 μL hand, petroleum ether and water fractions exhibited no antibacterial
and 1 mg/50 μL), and the antibacterial properties of the extracts activity. Phytochemical compositions of ethanol and ethyl acetate
against five bacteria, including Streptococcus pyogenes (S. pyogenes), extracts were similar, including flavonoids, terpenoids, and phen-
Streptococcus pneumoniae (S. pneumoniae), P. aeruginosa, S. aureus, olic acids, which may result in the antibacterial activities of extracts
and Streptococcus mutans (S. mutans), were tested by the agar well (Rantsev-Kartinov, 2005; Shi et al., 2008; Qiao and Sun, 2014). From
diffusion method. The DCM extracts had the maximum IZD against the perspective of MIC, the ethyl acetate extracts showed lower MIC
S. pyogenes (IZD, 28.67 mm and 29.00 mm) but showed no inhib- values than the ethanol extracts, and the ethyl acetate fractions were
ition on S. pneumonia, while the other extracts all had antibacterial more effective against Gram-positive bacteria (lowest 62.5 μg/mL)
activities against S. pneumonia. Notably, P. aeruginosa was resistive compared to Gram-negative bacteria (lowest 125 μg/mL), which was
to all extracts, but S. pyogenes and S. aureus were sensitive. Similarly, perhaps a result of the barrier function of the cell membrane (Nikaido,
antibacterial effects of ethanol and water extracts of dandelion roots 1994; Gao et al., 1999; Ghaima et al., 2013).
were investigated against three Gram-positive (B. cereus, MRSA, Three novel antibacterial peptides designated ToAMP1, ToAMP2,
and S. aureus) and two Gram-negative (E. coli and S. typhimurium) and ToAMP3 were purified from dandelion flowers, which were cat-
strains (Kenny et al., 2014). Ethanol extracts showed significant inhib- ionic and cysteine-rich and consisted of 38, 44, and 42 amino acid
ition on three Gram-positive bacteria with MIC values of 250 μg/mL residues, respectively (Astafieva et al., 2012). The peptides at 6 μg/μL
and 375 μg/mL, while ethanol and water extracts did not inhibit produced a considerable antibacterial effect against Pseudomonas
the growth of Gram-negative strains. The water extracts contained syringae (IZD, 7–8 mm) and B. subtilis (IZD, 3–5 mm).
sugars and glycosidic compounds, which might serve as a potential
feed source to promote bacteria proliferation. In another study of Dandelion stems
Kenny and colleagues (Kenny et al., 2015), in order to further re- According to the research of Amin et al. (2016), dandelion stems
search the antibacterial activity of dandelion roots, the antibacterial were extracted by four extraction solvents (DCM, ethyl acetate,
activity of normal phase (NP) fractionations of methanol hydro- methanol, and water; 0.5 mg/50 μL and 1 mg/50 μL, respectively)
phobic extracts were also investigated. and the antibacterial properties of each extraction against five
As mentioned by Kenny et al. (2015), the further NP fraction- bacteria (S. pyogenes, S. pneumonia, P. aeruginosa, S. aureus, and
ations of NPF4 and NPF406 were identified by liquid chroma- S. mutans) were tested by the agar well diffusion method. The
tography solid-phase extraction NMR. The active compounds methanol extracts had the biggest inhibition zone diameter against
contained vanillin, coniferaldehyde, p-methoxyphenylglyoxylic acid, S. aureus (IZD, 21.33 mm and 23.33 mm), and only the methanol
9-hydroxyoctadecatrienoic acid, and 9-hydroxyoctadecadienoic extracts were active against S. pneumonia. However, P. aeruginosa
acid. In the previous study (Kenny et al., 2014), Kenny and was resistive to all stem extracts. Moreover, it was indicated that
co-workers also studied the phenolic constituents of ethanol extracts sesquiterpene lactones, triterpenes, phenolic acids, flavonoids, and
by ultaperformance liquic chromatography–tandem mass spectrom- coumarins might be the main active ingredients in the extracts of
etry and found 11 kinds of phenolics, mainly including chlorogenic dandelion stems (González-Castejón et al., 2012).
8 K. Chen et al.
Comparison of different dandelion parts and various extrac- dried roots or leaves of Taraxacum spp. is 4–10 g, while fresh roots
tion solvents may draw the following conclusions: roots are the or leaves can be consumed as food at levels of 50 g or more per day
most effective parts in inhibiting the growth of bacteria followed (Yarnell and Abascal, 2009).
by flowers, while stems are the weakest parts. In addition, the In the USA, typical doses of root or leaf tinctures are 3–5 mL, 3
methanolic extracts bear the highest antibacterial activity, following times per day, and the British Herbal Pharmacopoeia recommends
by ethyl acetate, DCM, and water. Different antibacterial potentials 0.5–2 g of root or 4–8 mL of root tincture, 3 times per day (Yarnell
of various extracts indicate that the solvents could extract the dif- and Abascal, 2009). In addition, the British Herbal Pharmacopoeia
ferent active compounds varying in number. Moreover, in this study, also advises 3–5 g of leaf or 5–10 mL of leaf tincture, 2 times per day.
the extracts of the plants extracted by highly polar organic solvents The German Commission E Monographs suggests doses of 3–4 g of
possessed higher antibacterial activity, which was also confirmed by root, 2 times per day, or 10–15 drops of tincture, 3 times per day
Ionescu et al. (2013). (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
Whole dandelion (Blumenthal et al., 1998).
Dandelion was extracted by hydrogen peroxide to obtain oligo- Dietary supplementation with dandelion extracts at 1 g/kg con-
saccharides, then the extraction conditions were optimized centration significantly improved intestinal immune ability and pro-
by response surface methodology to get the maximum yield of moted intestinal development, as well as increased intestinal physical
25.43 per cent oligosaccharides (Qian et al., 2014). Antibacterial barrier of golden pompano (Tan et al., 2018). When rats and mice
studies proved that oligosaccharides exhibited great antibac- were administered the ethanolic extracts of dried dandelion at a dose
terial effects against S. aureus (16.15 mm), E. coli (13.21 mm), of 10 g and 4 g of per kilogram body weight, the extracts exerted
and B. subtilis (12.04 mm). Polysaccharides could also be incorp- very low toxicity (Tita et al., 1993). Rabbits treated with 3–6 g/kg
orated into nanomaterials to improve the antibacterial activity. body weight of whole dried and powered dandelion plants showed
A water-soluble antibacterial polysaccharide from dandelion no visible signs of acute toxicity (such as restlessness, respiratory
(PD) was chemically modified to obtain its carboxymethylated distress, convulsions, coma, and death; Akhtar et al., 1985). Rats
derivative (CPD). The antibacterial effects of PD and CPD were fed with diets containing 33 per cent dandelion for months showed
studied by time-killing analysis and transmission electron micro- no toxic effects (Hirono et al., 1978). No negative effects in humans
scope, and the results indicated that the numbers of residual have been reported during pregnancy or lactation, in children, or
L. monocytogenes decreased when treated with 10 mg/mL PD in combination with pharmaceutical drugs (Yarnell and Abascal,
and CPD, and CPD had a greater antibacterial effect than PD; in 2009).
addition, cell membrane and cell integrity of bacteria were des-
troyed and CPD resulted in more severe damage. The enhanced Conclusion
antibacterial activities of CPD were attributed to the more stable Dandelion is an important TCM, which is usually extracted by
triple-helical structures (Liu et al., 2017). Subsequently, PD and methanol, ethanol, ethyl acetate, hexane, chloroform, and water to
CPD were incorporated into a polyethylene oxide (PEO) nanofiber obtain phytochemicals, and is often handled by cellulase-assisted ex-
matrix to fabricate antimicrobial nanofibers and then their anti- traction and hydrogen peroxide hydrolysis to generate dandelion-
bacterial effects were studied by the agar diffusion assay and the derived polysaccharides. It is known that many factors affect
plate count method. The results indicated that there was a high antibacterial activity, such as extraction solvents, sources of dan-
efficiency of bacterial control for both PD/PEO and CPD/PEO delion, the amounts of raw material, the extraction methods, and
nanofibers against L. monocytogenes. Moreover, T. laevigatum methods of test, which may result in the different antibacterial re-
was also used for the synthesis of platinum nanoparticles (PtNPs), sults in the above researches. Through the review of dandelion, we
and the biosynthesized PtNPs exhibited great antibacterial effect can conclude carefully that dandelion roots extracts have a better
against B. subtilis (15 mm) and P. aeruginosa (18 mm), and the antibacterial effect than other parts, and high polar organic solvents
MICs of PtNPs against B. subtilis and P. aeruginosa were 53.2 μg are the better choice to extract dandelion. Many kinds of bioactive
and 62.5 μg, respectively, which may be attributed to the small compounds but not only one contribute to the antibacterial activities
size, large surface area, uniform dispersion, and spherical morph- of dandelion, especially sesquiterpene lactones, flavonoids, phenolic
ology of PtNPs (Tahir et al., 2017). acids, tannins, and alkaloids. Although it is demonstrated prelim-
In the research of Gao (2010), T. mongolicum was extracted by inarily that the bacterial cell membrane or DNA might be one of
water and ethanol, and the water extracts showed no antibacterial the targets of action, the known mechanisms of dandelion against
effect and the ethanol extracts significantly inhibited the growth pathogens are limited. Thus, commercial products of dandelion ac-
of E. coli (MIC, 50 μg/mL), P. aeruginosa (MIC, 100 μg/mL), tive compounds are still to be developed, and meanwhile, more ex-
and S. aureus (MIC, 50 μg/mL). As summarized by the author, tensive and comprehensive studies are desperately needed to exploit
phenylpropanoids and sesquiterpene lactones were the key to anti- unknown mechanisms.
bacterial activity and they were insoluble in water.
Coptis rhizome
Dosage and toxicity C. rhizome, also known as Huanglian in Chinese, is the rhizome of
Dandelion extracts are listed on the U.S. Food and Drug Coptis chinensis franch, which is commonly used as a main TCM
Administration’s ‘generally recognized as safe’ list for foods and sup- to cure various diseases (Wang et al., 2019). In traditional Chinese
plements, which were found to pose little risk of harm (Yarnell and remedy, more than 32 000 Chinese Medical Formulas mention
Abascal, 2009). The low toxicity is probably ascribed to the absence C. rhizome, usually in the form of a powder, pill, decoction, or tablet
of any significant toxins or alkaloids (Schütz et al., 2006a). (Wang et al., 2019).
In humans, dandelion is consumed as a kind of food and there- Alkaloids are the main active compounds of C. rhizome, and
fore has a relatively low toxicity. The optimal daily dose of crude they control the quality of C. rhizome (Han et al., 2019). Among
them, isoquinoline alkaloids account for a large percentage, with berberine at subminimum inhibitory concentrations (1–64 μg/mL),
berberine as the most abundant composition. Common alkaloids no antibacterial activity was found, but berberine could prevent ag-
include berberine, coptisine, palmatine, jatrorrhizine, epiberberine, gregation of phenol-soluble modulins (PSMs) into amyloid fibrils in
magnoflorine, columbamine, oxyberberine, noroxyhydrastinine, MRSA to inhibit the formation of biofilm by disrupting intermo-
8-oxocoptisine, and berberubine (Huang et al., 2015; Qian et al., lecular attractions among PSM monomers and destabilizing the π–π
2015). Among them, the five alkaloids of berberine, coptisine, stacking of phenylalanine residues (Chu et al., 2016).
palmatine, jatrorrhizine, and epiberberine share the same structural After E. coli is exposed to berberine, it can form filaments,
skeletons, which indicate their similar basic properties. The struc- indicating the presence of inhibition of cell division. In order to test
tural differences among them are reflected in the different func- whether berberine inhibited cell division protein FtsZ, the effects
tional groups of C–2, C–3, C–9, and C–10, including –H, –CH2, of berberine on formation of the cell division Z-rings were tested
and –CH3. Apart from alkaloids, C. rhizome also contains lignans, (Boberek et al., 2010). The results showed a dramatic reduction in

phenylpropanoids, flavonoids, phenolic compounds, saccharides, Z-rings in the presence of berberine, which contributed to antibac-
steroids, organic acids, quinones, and other chemical compounds terial actions. Besides, RNA silencing of ftsZ genes of E. coli resulted
(Gao et al., 2011; Meng et al., 2018). in increased sensitivity of bacteria to drugs, while overexpression of
By far the most numerous systematic research has led to the con- ftsZ genes led to a mild rescue effect in berberine-treated cells. Sun
clusion that C. rhizome exerts potent pharmacological effects in et al. (2014) designed and characterized berberine-based FtsZ inhibi-
various diseases (Gao et al., 2020) because of its antibacterial ac- tors with broad-spectrum antibacterial activities.
tivity (Zhang et al., 2010), hypoglycemic action (Pan et al., 2019), A whole-genome DNA microarray was conducted to investigate
anticancer effect (Liu et al., 2015), anti-inflammation function (Chen the transcriptome analysis of Yersinia pestis (Y. pestis; Zhang et al.,
et al., 2017), lipid-lowering potential (Sun et al., 2017; Zhou et al., 2009) and Shigella flexneri (S. flexneri; Fu et al., 2010) in response to
2017), and anti-atherosclerotic potential (Hitt et al., 2017). 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,
Antibacterial activities of C. rhizome
and genes encoding cellular envelope and related to iron uptake,
The alkaloids of C. rhizome have been proved to be the main
while 27 genes were downregulated. For S. flexneri, a total of 397
constituents against pathogens, and the antibacterial activities of
genes were disparately expressed, 164 genes were upregulated, such
different alkaloids are detailed in this part. A summary of the anti-
as genes associated with cell division, chromosome partitioning,
bacterial activities is presented in Table 2, and the profile of the anti-
translation apparatus, DNA replication and repair, cell envelope bio-
bacterial activities is shown in Figure 3.
genesis, and lipid metabolism, while 233 genes were downregulated,
for example, genes concerned with energy production and conver-
Berberine sion, amino acid metabolism, carbohydrate metabolism. The dif-
Berberine, with molecular formula C20H19NO5, a 5,6-dihydro- ferences in results reflected the discrepant expression situation of
dibenzo [a,g] quinolizinium derivative, is an isoquinoline quaternary metabolism genes. Most of the metabolism genes of Y. pestis were
alkaloid from many kinds of medicinal plants. Berberine possesses upregulated by berberine, while the metabolism genes of S. flexneri
multiple pharmacological effects, including antigastroenteritis, showed different changing trends. In another study (Du et al., 2020),
antidiabetic, anticancer activities, and so on. Of course, antibacterial quantitative proteomics was used to study the action mechanisms of
activity is one of the most important. berberine against S. pyogenes, which found similar conclusions to Fu
It was reported that the absolute oral bioavailability of berberine et al. (2010). In addition, it was shown that reactive oxygen species
was really low, while the concentration in liver was approximately were induced by berberine to damage macromolecular biosynthesis
70-fold greater than in plasma (Liu et al., 2010), which attributed to to trigger cell death. According to Yi et al. (2007), the metabolic
liver organic cation transport and organic anion transporting poly- profiles of S. aureus treated by berberine and 9 other antibacterial
peptides (Chen et al., 2015). However, the various biological activities substances were obtained by high-performance liquid chromatog-
of berberine in vivo were achieved by the transformation of berberine raphy–mass spectrometry (HPLC-MS), and principal component
into other active compounds through different metabolic pathways, analysis was carried out to investigate berberine’s possible antibac-
mainly including sulfation, demethylation, reduction, methylation, terial modes. Results indicated that the antibacterial modes were
demethylenation, and hydroxylation (Wang et al., 2017), or realized similar to rifampicin and norfloxacin, which act on nucleic acid,
by the conversion of berberine into dihydroberberine via gut micro- such as RNA polymerase, gyrase, and topoisomerase IV.
biota (Feng et al., 2015). Microcalorimetry, which has been used successfully to evaluate
MRSA has been an important hospital and community pathogen the effect of C. rhizome on microbial metabolism, was able to offer
with multidrug resistance, the cause of the resistance being the genes dynamic energy metabolism information with the flow of thermal
located mainly in the mec region of the MRSA chromosome (Shiota effect and continuously recorded the signal for a long time without
et al., 1999). Berberine exhibited great antibacterial activity against any system disturbance (Feng et al., 2011). It could be seen from
all tested MRSA strains with MIC from 32 μg/mL to 128 μg/mL, heat flow power (HFP)–time curves that the growth metabolisms of
and the possible action of berberine may be inhibition of the gene Streptococcus dysenteriae were inhibited by berberine, and the max-
expression (Yu et al., 2005). As we know, bacterial adhesion and imum HFP and total heat output were decreased with an increasing
invasion into cells are one of the most common pathogenic mechan- concentration of berberine (Kong et al., 2010). Meanwhile,
isms, and it has been proved that berberine could block the adhesion microcalorimetry was used to investigate the effects of berberine on
of S. pyogenes and E. coli to host cells (Sun et al., 1988a, 1988b). E. coli, B. subtilis, and their mixtures (Kong et al., 2012). A low
Meanwhile, in the above studies, MRSA adhesion and intracellular concentration of berberine (20 μg/mL) could inhibit the growth of
invasion into human gingival fibroblasts were notably decreased E. coli and the mixture of E. coli and B. subtilis. Interestingly, a low
in the presence of 1–50 μg/mL berberine. In another study, with concentration of berberine could promote the growth of B. subtilis,
Table 2. Summary of antibacterial activities of alkaloids from C. rhizome
10
Type of Extract Antibacterial result Related mechanism Reference

alkaloids solvent
Berberine Purchased MRSA (MICs, 32–128 μg/mL) Berberine could inhibit the mec region of MRSA chromosome, Yu et al. (2005)
MRSA (IZD, 17–26 mm) lower the MICs of ampicillin and oxacillin against MRSA, and
MRSA OMS7 (MIC, 4 μg/mL) (32 μg/mL berberine+ampicillin) decrease MRSA adhesion and intracellular invasion
MRSA OMS7 (MIC, 1 μg/mL) (32 μg/mL berberine combines+oxacillin)
MRSA ATCC 25923 (MIC, 0.016 μg/mL) (64 μg/mL berberine+ampicillin)
MRSA ATCC 25923 (MIC, 0.008 μg/mL) (64 μg/mL berberine+oxacillin)
Ethanol Salmonella strain CVCC528 (MIC, 3125 μg/mL) Berberine could decrease the expressions of LuxS, rpoE, and Shi et al. (2018)
Multiresistant Salmonella strain (MIC, 3125 μg/mL) ompR, which were related to the formation of biofilm
Multiresistant Salmonella strain+ciprofloxacin (MIC, 1562 μg/mL)
Purchased E. coli strain K-12 (RNA silencing of FtsZ) (MIC, 1.5 mmol/L) Berberine could inhibit cell division protein FtsZ, which wasd Boberek et al. (2010)
reflected in dramatic reduction in Z-rings
Purchased Method: microcalorimetry The functional groups methylenedioxy at C–2 and C–3 on Fan et al. (2008), Kong
S. aureus: phenyl ring improved antibacterial activity more remarkably et al. (2009), Yan et al.
berberine>coptisine>palmatine>epiberberine>jatrorrhizine than methoxyl at C–2 and C–3 on the phenyl ring, while (2008, 2009)
E. coli: methylenedioxy or methoxyl at C–9 and C–-10 did not vary
berberine>coptisine>palmatine significantly. Besides, berberine mainly acted on harmful bac-
B. shigae, E. coli: teria
berberine>coptisine>palmatine
B. adolescentis:
palmatine>coptisine>berberine
E. coli:
berberine>coptisine>palmatine>jatrorrhizine
Purchased MRSA (MIC, 128 μg/mL) Berberine could affect phenol-soluble modulins aggregation Chu et al. (2016)
into amyloid fibrils to inhibit the biofilm formation of MRSA
Purchased Method: microcalorimetry NR Kong et al. (2010,
S. dysenteriae 2012)
E. coli
B. subtilis
Purchased Treatment with berberine significantly increased the survival rate of mice By comparing with LPS, berberine could present higher affinity Chu et al. (2014)
challenged with S. typhimurium to the TLR4/MD-2 receptor to reduce the production of in-
flammatory factors to achieve antibacterial effect
Purchased Method: HPLC-MS and principal component analysis Berberine might act on nucleic acid, such as RNA polymerase, Yi et al. (2007)
S. aureus gyrase, and topoisomerase IV
Purchased H. pylori (MICs, 100–200 μg/mL) Berberine could inhibit the expression of efflux pump hefA Huang et al. (2015)
mRNA
Purchased Method: a multi-omics study Berberine could trigger DNA replication/repair and transcrip- Karaosmanoglu et al.
E. coli tion, destroy the cell membrane and motility-related functions, (2014)
and repress genes of metabolisms
Purchased MRSA 4806 (MIC, 32 μg/mL, berberine) Berberine could inhibit the biofilm formation and destroy ma- Liang et al. (2014)
MRSA 4806 (MIC, 1024 μg/mL, fusidic acid) ture biofilm
MRSA (MICs, 0.0625–8 μg/mL, berberine+fusidic acid)
Purchased MRSA (MIC, 32–128 μg/mL) NR Zuo et al. (2012)
K. Chen et al.

Table 2. Continued
Type of Extract Antibacterial result Related mechanism Reference

alkaloids solvent
Coptisine Purchased H. pylori standard strain (MIC, 25 μg/mL) Coptisine could play the anti-H. pylori effect by inhibiting the Li et al. (2018)
H. pylori strains (MICs, 25–50 μg/mL) activity of urease. Sulfhydryl group was the main action site of
coptisine in urease. Coptisine interfered with urease maturation
by inhibiting activity of prototypical urease accessory protein
UreG and formation of UreG dimers and by promoting dissoci-
ation of nickel from UreG dimers
Palmatine Purchased H. pylori strains (MICs, 100–200 μg/mL, pH 7.4) The inhibition of palmatine on the urease was reversible Zhou et al. (2017)
H. pylori strains (MICs, 75–100 μg/mL, pH 5.3) and the sulfhydryl groups were the main sites of action of
Antimicrobial properties of several plants widely used in TCM
Urease of H. pylori (IC50, 0.53 mmol/L) palmatine. The molecular docking study proved that palmatine
interacted with sulfhydryl groups through N–H=π interaction
Epiberberine Purchased Urease of H. pylori (IC50, 3.0 μmol/L) The bond of epiberberine with urease was reversible and the Tan et al. (2017)
sulfhydryl groups were the main acting points by epiberberine.
As researched in molecular docking studies, 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
B. adolescentis, Bifidobacterium adolescentis; B. shigae, Bacillus shigae; B. subtilis, Bacillus subtilis; HPLC-MS, high-performance liquid chromatography–mass spectrometry; IC50, half maximal inhibitory concentration;
IZD, inhibition zone diameter; minimum inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus; NR, no research; C. rhizome, Coptis rhizome; E. coli, Escherichia coli; S. aureus, Staphylococcus aureus;
S. dysenteriae, Shigella dysenteriae; H. pylori, Helicobacter lipopolysaccharide.
11

12 K. Chen et al.

Figure 3. The profile of antibacterial effects of isoquinoline alkaloids from Coptis rhizome. LPS, lipopolysaccharide
while a high concentration (over 100 μg/mL) could inhibit it. Results ompR mRNA (Shi et al., 2018). The different antibacterial results
showed that E. coli could decrease the endurance of B. subtilis to of berberine in combination with various antibiotics were attributed
berberine and the growth characters of B. subtilis would not be pre- to the block of different bacterial resistance mechanisms, which was
sent in their mixture, which might attribute to the inhibitory effects proved to be a promising approach to solve current antibacterial
of E. coli on B. subtilis. agents’ resistance (Zuo et al., 2012).
Lipopolysaccharide (LPS), a kind of endotoxin, triggers the Li et al. (2019) designed two natural self-assembling modes
signal transduction pathway leading to inflammatory reaction by using berberine and flavonoid glycosides: nanoparticles (NPs) and
binding to the TLR4/MD-2 receptor via hydrophobic interaction, nanofibers (NFs); they first formed a one-dimensional complex
and its immune activating abilities are attributed to the lipid A unit unit and subsequently self-assembled into three-dimensional
(Salomao et al., 2012; Lacatus, 2013). The survival rate of mice in- nanostructures. NPs with the hydrophilic glucuronic acid toward
fected by S. typhimurium significantly improved after treatment with the outside exhibited significantly more antibacterial activity against
increasing concentration of berberine (Chu et al., 2014). In addition, S. aureus and biofilm removal ability than berberine, whereas NFs
berberine was able to reduce the mortality rate of mice challenged showed a weaker effect than berberine. In addition, self-assembled
with LPS and delay their death time. Meanwhile, berberine treat- nanostructures had good biocompatibility proved by hemolysis tests,
ment lowered the increasing body temperature of rabbits challenged cytotoxicity tests, and zebrafish toxicity evaluation. The evaporative
with LPS. The molecular mechanism studies that followed showed precipitation of nanosuspension (EPN) and antisolvent precipitation
that berberine presented higher affinity to the TLR4/MD-2 receptor with a syringe pump (APSP) methods were used to synthesize ber-
to block the signaling in comparison with LPS. berine nanoparticles, respectively, which had increased solubility and
With the increasing use of antibiotics and the emergence of dissolution rate by the conversion of the crystalline structure to a
bacterial drug resistance, much attention has been focused on semicrystalline form (Sahibzada et al., 2018). Moreover, berberine
traditional Chinese herbal medications in combination with anti- NPs exhibited superior antibacterial activities against S. aureus,
biotics to achieve drug synergy, enhance efficacy, and reduce tox- E. coli, P. aeruginosa, and B. subtilis, and NPs synthesized by the
icity (Sharma et al., 2010). Berberine could significantly lower the EPN method showed a better effect than those by the APSP method.
MICs of antibiotics against MRSA; an additive effect was found be- In addition, the aqueous extracts of C. rhizome were used to
tween berberine and ampicillin and a synergistic effect was found synthesize silver nanoparticles (Pei et al., 2019) and form nanofibers
between berberine and oxacillin against MRSA (Yu et al., 2005); with poly(vinyl alcohol) (Yang et al., 2018). They were proved
a synergistic action was found between fusidic acid and berberine to exhibit significant antibacterial activities against B. subtilis,
against MRSA (Liang et al., 2014); synergies were observed for the P. aeruginosa, S. aureus, and K. pneumoniae. Compared with the
berberine/azithromycin and berberine/levofloxacin combinations compounds themselves, the nanoparticles showed higher antibac-
against MRSA; and an additivity result was observed for the ber- terial activities, which may be due to their size and large surface area.
berine/azithromycin combination against MRSA (Zuo et al., 2012).
Additionally, a synergistic inhibition effect was found between ber- Coptisine
berine and ciprofloxacin on the biofilm formation of a multiresistant Coptisine, with the molecular formula C19H14NO4, derived from
Salmonella strain by repressing the expressions of luxS, rpoE, and benzylisoquinolines through phenolic oxidation and coupling with
the isoquinoline N-methyl group, is a typical quaternary proberberine Epiberberine

alkaloid from C. rhizome (Wang et al., 2019). Coptisine possesses Epiberberine, with the molecular formula of C20H18NO4, is a
multiple pharmacological effects, including anticancer, antibacterial, natural protoberberine from the C. rhizome. Epiberberine has
anti-inflammatory effects, and so on (Wu et al., 2019). many pharmacological functions, including antibacterial, anti-
Urease is critical to the colonization and virulence of adipogenic, anticancer, antidyslipidemia activities, and so on (Liu
Helicobacter pylori (H. pylori), and can catalyze the hydrolysis et al., 2020).
of urea to ammonia to create an alkaline local environment re- The urease inhibitory activities of five alkaloids in C. rhi-
quired for the survival of H. pylori (Zeer-Wanklyn and Zamble, zome, including berberine, coptisine, epiberberine, palmatine, and
2017). The binuclear nickel ions existing in the active site and jateorhizine, were investigated by comparing the half maximal
sulfhydryl groups are essential for its catalytic activity (Krajewska inhibitory concentration (IC50) values (Tan et al., 2017). The re-
and Zaborska, 2007; Kumar and Kayastha, 2010). Coptisine had sults showed that the inhibition against urease was concentration-

remarkable antibacterial activities against H. pylori with MICs dependent inactivation, and epiberberine was the strongest inhibitor,
of 25–50 μg/mL, and urease inhibitory activities were achieved which was even more effective than the standard urease inhibitor,
by binding to the urease active site sulfhydryl group and nickel acetohydroxamic acid. According to their inhibitory ability, the
metallocenter (Li et al., 2018). The H. pylori urease inhibition in- five alkaloids ranked as follows: epiberberine, palmatine, coptisine,
duced by coptisine was mixed-type. According to the reaction pro- jateorhizine, berberine. The H. pylori urease inhibition induced by
gress curves of coptisine and urease, the binding process involved epiberberine was slow-binding and uncompetitive. Furthermore,
the rapid formation of a collision complex that then underwent the active site sulfhydryl group of ureases played an important role
a slow conversion into a more stable final complex. Additionally, in inhibiting progress and the inhibition was reversible. Molecular
after adding dithiothreitol, the activities of coptisine-inhibited docking studies further investigated the binding mode between
urease were partially restored, which proved that coptisine-induced epiberberine and urease, 9-O-CH2 and 2-O-CH3 of epiberberine
inhibition of urease was reversible. formed strong N–H≡O hydrogen bond to the backbone with the
As proved by in vivo study, coptisine interfered with urease backbone H atom of Met-366 and Asn-168, respectively.
maturation by inhibiting the activity of prototypical urease acces- Besides those above, jatrorrhizine, as one of the alkaloids, also
sory protein UreG and the formation of UreG dimers, and by pro- proved to have antibacterial activities. Yu et al. (2019) performed
moting dissociation of nickel form UreG dimers. Besides, according a checkerboard microdilution assay and used a murine thigh infec-
to molecular docking study, the coptisine 3–O–CH2– group formed tion model to investigate the synergistic effect of jatrorrhizine and
hydrogen bond interactions with the NH group of His-221 at a norfloxacin against MRSA for in vitro and in vivo assays, respect-
distance of 2.2×10-10 m, and the benzene rings of coptisine might ively. The MIC of jatrorrhizine against MRSA was 64 mg/L. A syn-
form hydrophobic interactions with Ala-169, Ala-365, Met-366, ergistic effect was achieved between jatrorrhizine and norfloxacin
His-322, Cys-321, and His-323. with fractional inhibitory concentration index (FICI) of 0.375. A re-
verse transcription semiquantitative polymerase chain reaction and
Palmatine a molecular docking study were conducted to explain the synergistic
Palmatine, with the molecular formula C21H22NO4, is a naturally effects. It was indicated that jatrorrhizine could suppress the expres-
occurring isoquinoline alkaloid found in many TCMs. Palmatine sion of bacterial drug efflux NorA, and could bind to NorA through
has many pharmacological functions, including neuroprotective, hydrogen bonds, and hydrophobic and electrostatic interactions.
anticancer, antibacterial, anti-inflammatory effects, and so on (Long In comparison with berberine, there are relatively fewer
et al., 2019). studies about the antibacterial activities of coptisine, palmatine,
The MIC values of palmatine against 4 tested H. pylori strains epiberberine, and jatrorrhizine. Microcalorimetry was used to in-
were measured by the agar dilution test, and MIC values were vestigate the antibacterial activities of these four alkaloids from
100–200 μg/mL and 75–100 μg/mL under neutral and acidic con- C. rhizome (Feng et al., 2011). According to the results of Fan et al.
ditions, respectively, which proved the potential of palmatine acting (2008), the four alkaloids all showed significant antibacterial effects
as a beneficial therapy for H. pylori infection (Zhou et al., 2017). against S. aureus. As reflected in the power–time curves of S. aureus
Urease inhibitory activity of palmatine was implemented by binding growth in the presence of each alkaloid, the time of the lag phase of
to the urease active site sulfhydryl group, and the inhibition process bacteria growth (tp) was prolonged, and the maximum heat output
was reversible. Kinetic analyses indicated that the urease inhibition (Pmax) decreased after treatment, which indicated that all four alkal-
by palmatine was noncompetitive. oids could inhibit the growth of S. aureus. Moreover, the antibac-
Further molecular docking research showed that palmatine in- terial effects of coptisine, palmatine, and jatrorrhizine against E. coli
hibited the active enzymatic conformation through N–H=π inter- (Yan et al., 2008, 2009; Kong et al., 2009) and Bacillus shigae (B.
action, but did not interact with the active site Ni2+, which was shigae) (Yan et al., 2009) were also proved by microcalorimetry.
different to coptisine. From the docking conformation, 2-OCH3 of
palmatine, which was the hydrogen bond donor, formed O–H≡N Intercomparison
hydrogen bond (H≡N distance=2.1×10-10 m) to the OH and the As summarized above, C. rhizome alkaloids have been widely
backbone N atom of Arg-339 of the active site of the enzyme. proved to exert significant antibacterial activities against common
As summarized by previous articles (Thakur et al., 2016; Long gastrointestinal pathogens. The ability of antibacterial activities of
et al., 2019), the potential antibacterial mechanisms of palmatine alkaloids against pathogens, such as S. aureus (Fan et al., 2008),
might involve insertion of bacterial DNA, inhibition of protein bio- E. coli (Yan et al., 2008, 2009; Kong et al., 2009), and B. shigae
synthesis, inhibition of DNA synthesis, inhibition of topoisomerase, (Yan et al., 2009), was investigated by comparing calorimetric data
prevention of cell proliferation, mitochondrial rupture/depolariza- from power–time curves obtained by microcalorimetry. The order
tion, and induction of bacterial apoptosis. of their antibacterial activities was berberine>coptisine>palmatine>
14 K. Chen et al.
epiberberine>jatrorrhizine. However, the order of alkaloids against remarkable clinical signs were seen and no adverse effects were
MRSA obtained by broth microdilution method was berberine>co found on rats administered with C. rhizome during the study (Lee
ptisine>jatrorrhizine>palmatine>epiberberine, which was different et al., 2014).
from the above results (Luo et al., 2013). Besides, the sequence
of antimicrobial activities of alkaloids against Bifidobacterium Conclusion
adolescentis was also studied by microcalorimetry, and the result It is well known that five isoquinoline alkaloids in C. rhizome, ber-
was palmatine>coptisine>berberine (Luo et al., 2013). berine, coptisine, palmatine, epiberberine, and jatrorrhizine, are
In conclusion, the different antibacterial effects of alkaloids against the main contributors to its activities and functions. Among them,
bacteria were attributed to various alkaloid structures. According berberine is the most studied and possessed the best antibacterial
to the research results, the functional groups methylenedioxy and activity. In addition, different alkaloids exert diverse antibacterial
methoxyl at C–2 and C–3 on the phenol ring might be the major effects against pathogens, which may be attributed to the various

group contributed to the activities of alkaloids, and methylenedioxy substituent groups on the phenol ring of alkaloids. The alkaloids
at C–2 and C–3 on the phenyl ring improved antibacterial activ- used in antibacterial experiments are commonly commercially pur-
ities more remarkably than methoxyl (Yan et al., 2008, 2009; Kong chased, which is different from dandelion, and this may ascribe to
et al., 2009). Besides, when the compounds bear the same func- the difficulty of extraction and the low purity of extracts. Besides,
tional group at C–2 and C–3, a methoxy at C–9 and C–10 showed microcalorimetry has been used as a mature method in investigating
higher activity than methylenedioxy (Kong et al., 2009). However, the antibacterial effects of alkaloids. To sum up, isoquinoline alkal-
according to the results of Kong et al. (2009), substituent groups oids of C. rhizome have been proved to be potent in killing common
at C–9 and C–10 on the phenyl ring did not affect the antibacterial bacteria and have potential application values in food and medicine.
activities. Additionally, a synergetic effect against MRSA was found
between berberine and epiberberine, jatrorrhizine and palmatine, Scutellaria baicalensis
jatrorrhizine and coptisine, but an antagonistic effect against MRSA
S. baicalensis is the member of the genus Lamiaceae, which are per-
was found between coptisine and epiberberine (Luo et al., 2013).
ennial plants and include about 350 species. It is also known as
The optimal combination of five alkaloids was berberine: coptisine:
Huang-Qin in China and its roots are the main parts commonly used
jatrorrhizine:palmatine:epiberberine=0.702:0.863:1:0.491:0.526,
in TCM. Nowadays, the plants are widely cultivated in Shandong
which exerted significant antibacterial activities in the inhibition of
Province, Hebei Province, Shanxi Province, Gansu Province, and
MRSA infected mouse model (Luo et al., 2013).
Inner Mongonia Autonomous Region of China (Wang et al., 2018).
More than 295 compounds have been isolated from S. baicalensis,
Dosage and toxicity including flavonoids, terpenoids, polysaccharides, and other com-
The bioactivity of berberine alkaloids by oral administration was pounds. Of those, baicalin, baicalein, wogonin, and oroxylin A were
very low, and the plasma concentration of alkaloids displayed an the main active compositions (Li et al., 2004; Shang et al., 2010;
explicit nonliner relationship with oral dosage (Feng et al., 2015; Lu et al., 2011). High-performance liquid chromatography (HPLC),
Wu et al., 2019). As summarized by Wu et al. (2019), a daily single thin-layer chromatography, mass spectrometry (MS), GC-MS, and
dose of coptisine was 1.5–40 g, and the doses of in vitro and in capillary electrophoresis are usually applied to study these chemical
vivo for coptisine were in the range of 0.06–468 μmol/L and compounds (Li et al., 2004).
0.0025–150 mg/kg, respectively. In China, S. baicalensis has a medicinal history of at least
The median lethal dosage (LD50) values of berberine by intra- 2000 years, and was used to treat various clinical diseases. Studies
venous injection, intraperitoneal injection and intragastric oral on its pharmacological effects showed that S. baicalensis possessed
administration in mice were 9.0386, 57.6103 mg/mg and none, re- anticancer activities (Bie et al., 2017), antibacterial and antivirus ef-
spectively (Kheir et al., 2010). According to Ma et al. (2010), the fects (Yang et al., 2005; Shi et al., 2016; Zhi et al., 2019), anti-inflam-
LD50 of the total extract of C. rhizome was 2.95 g/kg in mice, and matory activities (Feng et al., 2014; Kim et al., 2014), antidiabetic
they concluded that all alkaloids showed dose- and time-dependent functions (Shin et al., 2020), and the ability to maintain bile acid
cytotoxicity. In the acute toxicity study, LD50 of fibrous roots of homeostasis (Han et al., 2017).
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 Antibacterial activity of S. baicalensis
3.76 g/kg of body weight resulted in damage to liver and lung (Ning The antibacterial activities are mainly attributed to the presences of
et al., 2015). The LD50 values of berberine, coptisine, palmatine, and baicalein, baicalin, and volatile oil of S. baicalensis. A summary is
epiberberine were 713.57, 852.12, 1533.68, and 1360 mg/kg in presented in Table 3, and the profile of the antibacterial activities is
mice, respectively, and no mortality or morbidity were observed in shown in Figure 4.
the subchronic toxicity study (Yi et al., 2013).
In 1978, C. rhizome was implicated in causing neonatal jaundice Baicalein
and kernicterus in neonates suffering from glucose-6-phosphate de- It was reported that l-lactic acid, as a substrate recognized and util-
hydrogenase (G6PD) deficiency, leading to the banning of C. rhi- ized by H. pylori, was able to promote the growth and colonization
zome and berberine in Singapore. Later, after accumulating studies of H. pylori (Takahashi et al., 2007). Thus, a newly developed fluoro-
pointing to the safety of C. rhizome for the general public and better metric assay was developed by Takahashi et al. (2007) to screen the
understanding of G6PD deficiency, the Health Sciences Authority substances that had an inhibitory effect on l-lactic acid-dependent
in Singapore reviewed and lifted the prohibition of C. rhizome and H. pylori. Baicalein was proved to significantly inhibit the growth
berberine (Ho et al., 2014). There was no organ toxicity or elec- of l-lactic acid-dependent H. pylori, which was probably achieved
trolyte imbalance in 20 patients where C. rhizome was adminis- by influencing the l-lactic acid metabolic pathways of H. pylori. In a
tered for 1055 patient-days (Linn et al., 2012). No mortality or similar research (Chen et al., 2018), a lower concentration of baicalein
Table 3. Summary of antibacterial activities of S. baicalensis
Phytochemical Source Antibacterial result Related mechanism Reference

compound
Baicalein Baicalein was purchased l-Lactic acid-dependent and clarithromycin-sensitive Baicalein could influence the l-lactic acid metabolic path- Matsumoto et al. (2008)
commercially H. pylori (IC50, 0.5 μmol/L) way of H. pylori
l-Lactic acid-dependent and clarithromycin-resistant
H. pylori (IC50, 1.1 μmol/L)
Baicalein was purchased H. pylori Baicalein could inhibit the growth of H. pylori, suppress Chen et al. (2018)
commercially (16 μmol/L and 31.25 μmol/L) the expression of vacA genes, and decrease the adhesion
abilities
Baicalein was purchased Ciprofloxacin-resistant MRSA (MIC, 64–256 μg/mL) Baicalein could restore the antibacterial activity by Chan et al. (2011)
commercially Ciprofloxacin-susceptible MRSA (MIC, 32–64 μg/mL) inhibiting the NorA efflux pump and inhibiting the pyru-
Ciprofloxacin-resistant MRSA (FICI, 0.38–1.0, baicalein vate kinase of MRSA to reduce the amount of ATP
combined with ciprofloxacin)
Baicalein was purchased P. aeruginosa Baicalein could inhibit QS system-related genes Zeng et al. (2008)
commercially Inhibit the formation of biofilm, 20 μmol/L;
proteolysis of TraR protein, 4–40 mmol/L
Baicalein was purchased P. aeruginosa PAO1 (MIC, >1024 μg/mL) Baicalein could downregulate the transcription of QS- Luo et al. (2016)
commercially regulated genes and translation of QS-signaling molecules
Antimicrobial properties of several plants widely used in TCM
Baicalein was purchased S. aureus (antibiofilm, 32 μg/mL) Baicalein could inhibit the formation of biofilm and sup- Chen et al. (2016)
commercially press the expression of QS-related genes
Baicalein was purchased Clinical penicillinase-producing S. aureus (FICI, 0.14–0.38, Baicalein could inhibit the activity of penicillinase Qian et al. (2015)
commercially baicalein combined with penicillin G/amoxicillin)
Baicalein was purchased S. aureus Newman strain and S. aureus ATCC 29213 strain Baicalein did not significantly inhibit the growth of S. aur- Zhang et al. (2020)
commercially I (MIC, greater than 1024 μg/mL) eus, but attenuated the virulence of S. aureus by blocking
the coagulase of van Willebrand factor-binding protein
Baicalein was purchased S. typhimurium Baicalein could target S. typhimurium pathogenicity island 1 Tsou et al. (2016)
commercially A high-throughput assay type III secretion system effectors and translocases
Baicalin Baicalin was purchased P. aeruginosa (MIC, >1024 μg/mL) Baicalin could inhibit QS-controlled virulence phenotypes Luo et al. (2017)
commercially and genes to reduce the infection of bacteria
Baicalin was purchased E. coli (MIC, >100 μg/mL) Baicalin could decrease the Autoinducer 2 (AI-2) secretion, Peng et al. (2019)
commercially biofilm formation, and the expression of virulence genes
Baicalin was purchased S. typhimurium (MIC, >128 μg/mL) Baicalin could suppress the expression of Salmonella Wu et al. (2018)
commercially pathogenicity island 1 virulence associated genes
Baicalin was purchased E. coli and S. aureus (higher antibacterial ratio, baicalin NR Zhou et al. (2016)
commercially incorporated into silk)
Volatile oil Ether E. faecalis (MIC, 31.25 μg/mL), NR Pant et al. (2012)
K. pneumoniae, B. subtilis and S. enterica (MIC,
62.5 μg/mL)
ATP, adenosine triphosphate; E. faecalis, Enterococcus faecalis; FICI, fractional inhibitory concentration index; H. pylori, Helicobacter pylori; IC50, half maximal inhibitory concentration; IZD, inhibition zone diam-
eter; K. pneumonia, Klebsiella pneumonia; MIC, minimum inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus; NR, no research; P. aeruginosa, Pseudomonas aeruginosa; QS, quorum sensing; S.
baicalensis, Scutellaria baicalensis; S. aureus, Staphylococcus aureus; S. enterica, Salmonella enterica; S. typhimurium, Salmonella typhimurium.
15

16 K. Chen et al.

Figure 4. The profile of antibacterial effects of Scutellaria baicalensis. QS, quorum sensing.
(16 μmol/L) could suppress the expression of the vacA genes (a major of MRSA inhibited by baicalein could lead to the deficiency of adeno-
virulent factor of H. pylori) and inhibit the growth of H. pylori, and sine triphosphate (ATP; Chan et al., 2011). A synergetic activity was
31.25 μmol/L of baicalein could decrease the adhesion abilities of achieved against 20 clinical penicillinase-producing S. aureus when
H. pylori to human gastric adenocarcinoma (AGS) cells. According baicalein was combined with penicillin G/amoxicillin with FICI values
to a high-throughput assay conducted by Tsou et al. (2016), baicalein ranging from 0.14 to 0.38, which could be ascribed to the inhibition
could act on S. typhimurium pathogenicity island 1 (SPI-1) type III of penicillinase activities by baicalein (Qian et al., 2015). According
secretion system (T3SS) effectors and translocases, which was the key to the study of Peng et al. (2011), baicalein might inhibit the SOS-
virulence pathway of bacteria, to inhibit the bacterial invasion of epi- response in S. aureus induced by ciprofloxacin to decrease the anti-
thelial cells. Zeng et al. (2008) performed an automated docking pro- biotic resistance of S. aureus. Moreover, synergistic effects of baicalein
gram to search for quorum sensing (QS) inhibitors of P. aeruginosa. and tetracycline against MRSA (Fujita et al., 2013), baicalein and
The results indicated that although baicalein did not exert antibac- cefotaxime against K. pneumonia (Cai et al., 2016), and baicalein and
terial effects against P. aeruginosa, it significantly inhibited biofilm linezolid against MRSA (Liu et al., 2020) were also found.
formation at 20 μmol/L and promoted proteolysis of the signal re-
ceptor TraR protein at 4–40 mmol/L, which manifested the inhib- Baicalin
ition activities of baicalein on QS system. However, in another study, The QS circuit was important in controlling virulence factors and bio-
the MIC of baicalein against P. aeruginosa was over 1024 μg/mL film formation of P. aeruginosa, and experiments proved that baicalin
(Luo et al., 2016), and the sub-MIC concentration of baicalein could could inhibit virulence phenotypes (LasA protease, LasB elastase,
decrease the expression of QS-regulated virulence genes, including pyocyanin, rhamnolipid, motilities, and exotoxin A), and QS-regulatory
genes related to motility and biofilm formation. Moreover, Chen genes (lasl, lasR, rhll, rhlR, pqsR, and pqsA) to reduce the infection of
et al. (2016) proved that 32 μg of baicalein significantly exhibited P. aeruginosa (Luo et al., 2017). In another study (Peng et al., 2019),
antibiofilm effects against S. aureus in vitro, and decreased the gene baicalin was proved to inhibit the QS of E. coli by suppressing the
expressions of agrA, sarA, and ica in QS system. Baicalein could at- expression of virulence genes and inhibiting the formation of biofilm.
tenuate the virulence of S. aureus by blocking the coagulase of van In addition, baicalin could downregulate the expression of Toll-like re-
Willebrand factor-binding protein (vWbp), which was one of the ceptor (TLR2), and the phosphorylation of p53 in the mammary glands
key virulence factors, but did not significantly inhibit the growth of in S. aureus-induced mastitis (Guo et al., 2014). According to the study
S. aureus. Thermal shift and fluorescence quenching assays, molecular by Wang et al. (2018), baicalin was able to bind to the center of Sortase
dynamics simulations, and mutagenesis assays proved that baicalein B (SrtB), a crucial virulence factor of S. aureus, to decrease S. aureus in-
could directly bind to vWbp through the Asp-75 and Lys-80 residues fections. The antagonistic activities against S. typhimurium of baicalin
(Zhang et al., 2020). were also testified, and the MIC was >128 μg/mL, and transcription
A synergistic effect was found between baicalein and ciprofloxacin levels of Salmonella pathogenicity island 1 virulence-associated genes
against 12 of 20 clinical ciprofloxacin-resistant MRSA, and an additive were significantly decreased by baicalin.
effect was observed against ciprofloxacin-susceptible MRSA by the Furthermore, in the research of Zhou et al. (2016), baicalin was
checkerboard dilution test and time–kill assay. Baicalein could restore incorporated into silk to produce a hygiene-related and health tex-
the antibacterial activities of ciprofloxacin against MRSA, possibly by tile product, which had higher antibacterial effect against E. coli and
inhibiting the NorA efflux pump. Besides, the specific pyruvate kinase S. aureus than baicalin itself.
Volatile oil TCM, as an important natural source with a long history, is

Volatile oil was firstly identified by Fukuhara et al. through GC-MS, and a unique medicine in traditional Chinese treatment. In the era of
proved to exert significantly antibacterial activities against B. subtilis, widespread antibiotic resistance, the discovery of new, natural, safe,
Enterococcus faecalis, K. pneumoniae, and Salmonella enterica, with and effective antibacterial compounds opens a new area for solving
MIC values from 31.25 μg/mL to 125.0 μg/mL (Fukuhara et al., 1987; foodborne illness and overcoming antibiotic resistance. Thus, ex-
Pant et al., 2012). The principal contents of volatile oil included oxy- ploring natural materials from medicinal herbs has inspired a new
genated monoterpene hydrocarbons, linalool, and 1-octen-3-ol (Pant wave for the discovery of alternative and green antibacterial drugs.
et al., 2012), which might be the active components. Except for these In long-term research, although the potential of some natural prod-
above, there are relatively fewer studies about the antibacterial activ- ucts for bacteriostasis extracted from medicinal plants has been
ities of volatile oil, and the single active components with antibac- proved, the challenge of discovering new substances is still huge.
terial activities need to be purified and further studied. 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
Dosage and toxicity extracted unknown compounds. More attention and research are
The aqueous extracts of S. baicalensis had no significant effects in urgently needed to explore the antibacterial mechanisms of these
body weight, clinical symptoms and mortality on rabbits and guinea natural compounds, which will pave the way for seeking effective
pigs (Kim et al., 2013). According to the experiment of Yi et al. natural drugs or food additives. Thus, on the one hand, it is crucial
(2018), when male and female rats were fed the ethanol extract of to purify the active substances to investigate the antibacterial ac-
S. baicalensis at a dose of 2500 mg/kg/d, the liver tissue showed tivity and clarify the antibacterial mechanisms. On the other hand,
some adverse reactions but returned to normal after withdrawal, and advances in the field of natural products used for solving antibiotic
glucose, electrolyte, and lipid levels also showed some changes. In resistance need multidisciplinarity and the combination of various
addition, no other functional or organic lesions were found during technologies.
the treatment. On account of the excellent advantages of these plants used as
According to the summary of Zhao et al. (2019), although there antibacterial agents, undoubtedly, they will be a good substitute or
was no obvious adverse reaction after intake of S. baicalensis, it was adjuvant of antibiotics. However, before this, further endeavor is still
not suitable for people with spleen and stomach deficiency for its needed in the following aspects of exploiting abundant plants with
bitter and cold medicinal properties. outstanding antibacterial activities, determining the structures and
properties of natural products, and more importantly, clearly clari-
fying the deeper antibacterial mechanisms.
Conclusion
Baicalein and baicalin are the main flavonoids for the antibac-
terial effects of S. baicalensis. In the references above, baicalein and Author Contributions
baicalin were almost obtained commercially. Their possible antibac-
Zhaojie Li and Kun Chen: Conceptualization and methodology and valid-
terial mechanisms included inhibiting bacterial growth, reducing
ation; Kun Chen, Xiudan Hou, and Wei Wu: Investigation; Zhaojie Li, Wei
bacterial virulence, destroying the formation of bacterial biofilm, Wu, and Kun Chen: Writing original draft; Qingli Yang: Writing, review and
and decreasing bacterial adhesion abilities. Among them, QS-related editing, and supervision; Xiudan Hou and Wei Wu: Project administration;
virulence factors are one of the most important sites of action. It Zhaojie Li and Qingli Yang: Funding acquisition. All authors have read and
is noteworthy that baicalein and baicalin were also significantly agreed to the published version of the manuscript.
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 Funding
seems to be a promising novel effective synergistic antibacterial This work was supported by the National Science Foundation of Shandong
agent to solve the problems of antibiotic resistance. However, other Province (No. ZR2020MC217), the Breeding Plan of Shandong Provincial
antibacterial mechanisms still need to be further exploited. Qingchuang Research Team (No. 2019-135), China.
Conclusion and Outlook Conflict of Interest

According to the above statements, these three Chinese traditional The authors declare no conflict of interest.
medicines all bear significant antibacterial activity against common

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A Review: Antimicrobial Properties of Several Medicinal Plants Widely Used in Traditional Chinese Medicine

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Food Quality and Safety, 2021, 5, 1–22

A review: antimicrobial properties of several

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

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Table 1. Summary of antibacterial activities of dandelion extracts

Parts of Extract solvent Antibacterial activity Related mechanism Reference

Roots Methanol (2 mg/mL) S. aureus (MIC, 500 μg/mL) NR Kenny et al. (2015)

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Table 1. Continued

Parts of Extract solvent Antibacterial activity Related mechanism Reference

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Table 1. Continued

Parts of Extract solvent Antibacterial activity Related mechanism Reference

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Figure 2. The profile of antibacterial activities of Taraxacum officinale

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Type of Extract Antibacterial result Related mechanism Reference

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Type of Extract Antibacterial result Related mechanism Reference

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the isoquinoline N-methyl group, is a typical quaternary proberberine Epiberberine

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Phytochemical Source Antibacterial result Related mechanism Reference

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Volatile oil TCM, as an important natural source with a long history, is

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Conclusion and Outlook Conflict of Interest

medicines all bear significant antibacterial activity against common

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