Study on Ginseng Extract Good for Antibacterial

Antibiotic antibacterial has been greatly developed and researched in recent decades. Although its antibacterial effect is very effective, it still has shortcomings. After a long period of unreasonable use of antibiotics, it will increase the number of clinically resistant strains, accompanied by the enhancement of fungal and bacterial resistance, and the mortality rate of clinical infectious diseases is also increasing. In addition, antibiotics can cause allergic reactions, toxic reactions, superinfections or aggravate adverse reactions and other side effects[1]. Some commonly used antibiotics such as penicillin may induce other side effects. For example, aminoglycosides can be harmful to the kidneys and inner ear. Nowadays, the medical community is facing a major problem of bacterial resistance and infections caused by drug-resistant bacteria. Drug-resistant strains have now appeared in almost all antibacterial drugs, and it is urgent to find a solution to the problem of bacterial resistance [2].

Traditional Chinese medicine has a unique antibacterial mechanism in the treatment of bacterial infectious diseases, is not prone to drug resistance, and has the effect of reversing the development of drug resistance. Ginseng is a traditional Chinese medicinal herb known worldwide. It is rich in active ingredients and has comprehensive functions. With in-depth research on the active ingredients of ginseng, ginseng antibacterial activity has gradually attracted attention and become a research hotspot.

1 Advantages of traditional Chinese medicine in inhibiting bacteria

The medical community has always been committed to finding safe and effective antibacterial drugs. Compared with the various shortcomings of antibiotics, traditional Chinese medicine in inhibiting bacteria is showing its unique “charm”. Traditional Chinese medicine is widely available, natural, and inexpensive. It has the effects of anti-inflammatory, anti-viral, and regulating the immune function of the body. For this reason, traditional Chinese medicine in inhibiting bacteria has become one of the research hotspots[3]. China is a vast country with a wealth of precious Chinese medicinal herbs. These herbs have unique advantages in both infection control and modern medicine. Chinese medicine has a special way of taking medicine, which is natural, comes in a wide variety, and has a comprehensive mode of action [4].

The search for antibacterial drug resources from natural products and the screening of antibacterial drugs have attracted increasing attention from scholars at home and abroad. With the deepening of research on traditional Chinese medicine, it has been found that traditional Chinese medicine not only has antibacterial and bacteriostatic effects, but also has the effect of delaying and eliminating bacterial drug resistance [2, 5]. Zhang Yingluo et al. [6] studied the antibacterial activity of 15 traditional Chinese medicine ingredients against several pathogenic bacteria and found that extracts of Zanthoxylum bungeanum Maxim., Atractylodes lancea, Aquilaria sinensis, Artemisia vulgaris and Cardamomum zeylanicum had good antibacterial effects. In addition, multiple studies have shown that the active ingredients extracted from honeysuckle leaves, green tea, etc., also have good antibacterial activity [7-9].

2. Antibacterial mechanism of traditional Chinese medicine

Common Gram-positive drug-resistant bacteria in clinical settings include methicillin-resistant Staphylococcus aureus (MRSA). In China, the incidence of MRSA infections is high, and the proportion of drug-resistant Mycobacterium tuberculosis and Candida is also increasing [10].

The increasing number of drug-resistant bacteria poses great difficulties for clinical treatment, and these drug-resistant bacteria pose a great threat to human health. In the face of the ever-increasing number of drug-resistant bacteria and their growing drug resistance, early detection and the therapeutic advantages of traditional Chinese medicine are undoubtedly of paramount importance. At present, the antibacterial mechanism of traditional Chinese medicine mainly includes the following four aspects: 1) After damaging the integrity of the cell wall and cell membrane of the bacterial cell body or hindering the synthesis of the bacterial cell wall, the massive loss of contents from the cell will cause the cell wall to lose its defensive function, change the transport function of the membrane, and hinder the transmembrane information transmission [11].

Eventually, the bacteria burst in a hypotonic environment or die due to an imbalance in electrolyte balance. 2) Effect on bacterial protein synthesis. Proteins are the main bearers of life processes in cells and organisms. Proteins are involved in forming important parts of the body. Interaction with bacterial ribosomes inhibits protein synthesis, preventing the synthesis of proteins and enzymes essential for cell survival [11]. 3) Affects the synthesis of genetic material DNA or RNA, inhibiting the reproduction and growth of the bacteria, while also affecting the translation of mRNA to synthesize proteins, inhibiting the growth of the bacteria [11]. 4) Inhibits the formation of bacterial biofilms. Traditional Chinese medicine can effectively prevent and treat infections caused by bacterial biofilms. Relevant studies have shown that this is mainly achieved by inhibiting the glucosyltransferase necessary for biofilm formation to prevent biofilm formation [12], as well as regulating the molecular signal system of bacterial density perception (Quorum-sensing, QS).

3 Ginseng ingredients and functions

There are many types of traditional Chinese medicine, and ginseng is a perennial herb that is one of the traditional precious Chinese medicinal materials. The cultivation of ginseng has a history of more than 1,600 years, and large-scale cultivation has also been carried out for more than 400 years[13] . Ginsenosides are considered to be the main active ingredient of ginseng and have always been a hot research topic for scholars and drug developers at home and abroad. There is no significant difference between the various types of ginseng in terms of their use. All ginsengs contain ginsenosides, and the pharmacological activity of ginseng is often attributed to ginsenosides. Most research on the pharmacology of ginseng focuses on ginsenosides[14] .

Ginsenosides can be divided into different types (protopanaxadiol-type ginsenosides, protopanaxatriol-type ginsenosides and oleanolic acid-type ginsenosides) according to the aglycone. These three types of ginsenosides contain many different components. Some ginsenosides are not only found in the roots and leaves of ginseng, but also in other parts of the plant (such as stems and leaves, above-ground stems, flowers, buds, fruits, and seeds). In addition, ginsenosides are not only found in ginseng and red ginseng, but also in other traditional Chinese medicines (such as Korean ginseng, American ginseng, Panax notoginseng, and Gynostemma pentaphyllum) [15]. Li Yang et al. [16] stated in their research progress on the chemistry and pharmacological effects of ginseng that the main components of ginseng that exert antibacterial effects are ginsenosides, ginseng polypeptides, ginseng polysaccharides, and volatile oils. Chen Qun et al. [17] showed that ginseng polysaccharides have immunostimulatory and antitumor effects, and have a certain degree of bactericidal effect.

4. The bacteriostatic effect and research progress of ginsenosides

4.1. Research on ginsenosides inhibiting bacteria

There are various research methods and choices of bacteria for the research on the bacteriostatic effect of ginsenosides. The choice of different types of bacteria and methods is significantly related to the research results of bacteriostatic effect. As early as 1995, Li Zhiping et al. [18] used microcalorimetry to study the effect of ginseng on Staphylococcus aureus from the perspective of promoting bacterial metabolism, and obtained a curve showing the relationship between the growth rate of bacteria and the concentration of ginseng, which indicates that ginseng can promote the metabolism of Staphylococcus aureus.

Cao Junling et al. [19] investigated the effects of ginsenosides Rg1, Rd and Rb1 on the biological heat production of Escherichia coli. The results showed that ginsenoside Rd significantly inhibited the heat production of Escherichia coli, while the inhibitory effects of Rg1 and Rb1 were weaker. Explanation: Ginseng saponin Rd can inhibit Escherichia coli by regulating the energy metabolism of the bacteria. Some studies have shown that after ginseng extract and ginseng saponin Rbl are administered to cows, the antibody titer against Staphylococcus aureus in their bodies is higher, lymphocyte proliferation capacity becomes stronger, and the effect of the monomeric saponin Rbl is better, indicating that ginseng extract and Rb1 not only have a good antibacterial effect, but also reduce the inflammation caused by Staphylococcus aureus to a certain extent [20]. Clinical studies have also shown that in hospitalized patients with multidrug-resistant bacteria causing lower respiratory tract infections who were treated with Baihu Jia Ganshen Tang, although the pathogenic bacteria were not effectively eliminated, their fever symptoms improved to a certain extent, and the white blood cells in the body decreased significantly, indicating that the body's inflammation gradually decreased. Baihu Jia Ganshen Tang can inhibit and reduce the toxicity and vitality of multidrug-resistant bacteria, thus making them colonize the body [21].

Liu Fangfang et al. [22] studied the antibacterial mechanism of ginseng total saponins against Fusarium solani. The results showed that ginseng stem and leaf total saponins can inhibit bacterial activity by changing the permeability of the cell membrane, inducing the excretion of a large amount of proteins and intracellular substances in the bacteria. Dong Chunlei[23] used Escherichia coli and Staphylococcus aureus as test strains to study and compare the antibacterial effects of rhubarb acid, magnolol, baicalein and ginseng saponins (including ginsenosides and ginsenosides). The results showed that rhubarb acid, magnolol and baicalin have a corresponding inhibitory effect on Escherichia coli bacterial liquid. Ginseng saponins have a stronger inhibitory effect on Escherichia coli than the three. At the same time, by comparing the antibacterial effects of five protopanaxadiol saponin monomers, it was found that ginsenoside Rc has the best inhibitory effect on Escherichia coli. Other research results show that berberine hydrochloride, ginsenoside Rb1, baicalin and chlorogenic acid all have a certain degree of antibacterial activity against Escherichia coli and Staphylococcus aureus, and their antibacterial activity has a concentration-dependent effect. and ginsenoside Rb1 and berberine hydrochloride have a better bacteriostatic effect than chlorogenic acid and baicalin at the same drug concentration [24].

4.2 Ginsenoside inhibition of bacterial biofilm research

Bacteria with biofilms are highly resistant to antibiotics and the host immune defense system. The resistance exhibited by bacterial biofilms may be due to the action of some bacteria within the biofilm. Under specific survival conditions, these bacteria can acquire virulence genes, drug resistance genes, etc., thereby exhibiting a protective biofilm phenotype, which in turn alters various physiological functions such as multiple drug resistance [23]. Existing studies have shown that there are two specific drug resistance mechanisms: those that are due to the production of inactivating enzymes (or deactivating enzymes) by the bacteria and changes in the target site of the antibiotic, and those that are due to the impermeability of the bacterial cell membrane or the enhanced function of the pump-out system on the cell membrane and the formation of a bacterial biofilm. These mechanisms of drug resistance are often less specific, and it is more difficult to obtain effective drugs for the study of drugs for bacterial biofilms. [25] .

 At present, the increase in bacterial resistance, the increase in drug-resistant strains, and the difficulty in curing bacterial infections are all closely related to the formation of bacterial biofilms. Staphylococcus aureus in particular is prone to forming biofilms on surfaces such as soft tissues, endovascular devices, and medical devices, which makes treatment more difficult [26-27]. Antibiotics have a good bactericidal effect on bacteria, but the inhibitory effect on some bacterial biofilms is not significant. In addition, biofilms are prone to gene mutation under the action of sub-concentration antibiotics, inducing the production of drug-resistant genes, and enhancing the drug resistance of bacterial biofilms according to the characteristics of biofilm signal transduction [28]. Therefore, the resistance caused by biofilms blocking the function of antibiotics is currently a focus of research and also a difficult problem.

Dong Chunlei [23] found that ginsenoside has a weak inhibitory effect on Staphylococcus aureus biofilms, but a strong inhibitory effect on Escherichia coli biofilms, through the BBF model of Escherichia coli and Staphylococcus aureus. Ginsenosides Rc and Rb2 can effectively inhibit Escherichia coli biofilms. An Jihong et al. [29] studied the antibacterial mechanism of ginseng saponins against Staphylococcus aureus. The results showed that Rh2 had no significant effect on the proliferation of Staphylococcus aureus, but it could effectively inhibit the formation of Staphylococcus aureus biofilms by inhibiting the expression of the genes ica (ica A, ica B, ica C) through the regulation of polysaccharide adhesins, thereby inhibiting the adhesion ability of biofilms.

4.3 Ginseng saponins and other drugs have synergistic antibacterial effects

Zhang et al. [30] used ginseng saponin Rh2 in combination with ciprofloxacin to treat Staphylococcus aureus, and the results showed that Rh2 can promote the bactericidal effect of ciprofloxacin by inhibiting the expression of the NorA gene. Recent studies have found that sub-inhibitory concentrations of gentamicin, ciprofloxacin and vancomycin have no significant inhibitory effect on Staphylococcus aureus biofilms, but the combination of ginsenoside Rh2 and antibiotics can promote the inhibitory effect of the three antibiotics on biofilms, and have a synergistic effect on the inhibition of biofilms [29]. Dong Chunlei [23] studied and compared the antibacterial effects of ginsenosides in the study of the inhibitory effects of ginsenoside monomers and ginseng monomers in combination with other traditional Chinese medicine monomers on bacterial biofilms. not only proved that ginsenosides inhibit bacteria and bacterial biofilms, but also demonstrated that the combination of ginsenosides with drugs such as rhubarb acid, magnolol, and baicalein has a synergistic and additive effect, which can significantly enhance the ability to inhibit bacteria and bacterial biofilms.

5 Limitations and prospects of ginsenoside antibacterial research

Ginsenosides show strong activity in inhibiting bacteria and bacterial biofilms. They can help to solve the current problem of bacterial drug resistance, but there are still many limitations in the current research on ginsenosides. The existing research results have found that ginsenosides have a strong inhibitory effect on Escherichia coli and Escherichia coli bacterial biofilms, but they cannot completely eliminate them. Ginsenosides have a weak inhibitory effect on Staphylococcus aureus, and the inhibitory effect on many other bacteria is still unknown. In addition, due to the lack of in-depth research on the antibacterial methods of Chinese herbal medicines, there is currently no perfect in vitro antibacterial evaluation method that reflects the characteristics of traditional Chinese medicine. This is also a limitation of current research on ginsenosides.

The antibacterial properties of ginsenosides have different effects on different bacteria species. Different bacteria species have different drug resistance mechanisms and different degrees of drug resistance. The strength of the antibacterial effect is also related to other factors (such as the culture medium). In experiments, the results obtained in a culture medium established to simulate the in vivo environment showed that pathogenic bacteria have strong resistance to ginsenosides. However, the complex internal environment is difficult to fully simulate, and in vitro culture may encounter many phenomena that can interfere with the results. Studies of antibacterial activity in vitro are always affected by many factors, which can cause inconvenience and errors in research. Due to the differences in the experimental environment between in vivo and in vitro, there may be differences in the antibacterial effect of ginsenosides obtained from the experiments. Therefore, in vitro, it is necessary to simulate the in vivo environment as comprehensively as possible in order to better exert the antibacterial effect of ginsenosides.

At present, research on the antibacterial efficacy of individual ginsenosides has begun, but research on the composition and dosage of ginsenosides is still relatively weak, and these need to be strengthened in future research. Ginsenosides have a two-way regulatory effect, and how to achieve better expected therapeutic effects through the control of relevant conditions and the rational combination and use of drugs (compatibility) is also a key direction for future research. Conducting research on the antibacterial effects of ginsenosides and developing related new products is not only to meet the needs of clinical treatment, but also to benefit the further development of China's ginseng industry. Therefore, conducting research on the antibacterial mechanism of ginseng is essential for the development and utilization of ginseng. The mechanisms by which ginsenosides intervene in the regulation of bacterial density perception signaling systems, intracellular signal transduction, and the expression of related genes will be the focus of research on ginsenosides' intervention in the formation of bacterial biofilms.

References

[1] Huang Yulan. Discussion on clinical measures for adverse drug reactions and rational application of antibiotics [J]. Northern Pharmacy, 2017, 14(1): 145-6.

[2] Li Ruiming, Lei Zhaoxia. Strategies to combat bacterial resistance: research on the use of traditional Chinese medicine to delay and reverse bacterial resistance and treat infections caused by drug-resistant bacteria [J]. Medicine and Philosophy (Clinical Decision Forum Edition), 2006, 27(8): 45-7.

[3] Hu Jinting, Ma Ping, Chen Yao, et al. Recent research on the prevention and control of bacterial biofilms by traditional Chinese medicine and its active ingredients [J]. Asia-Pacific Traditional Medicine, 2016, 12(24): 59-61.

[4] Li Yana, Tao Qingchun. Research status and thinking of traditional Chinese medicine antibacterial [J]. International Journal of Laboratory Medicine, 2014, 35(2): 198-200.

[5] Qi Jianjun, Wang Wenlin, Li Shude. Effect of ginsenoside Rg1 on NOX3-induced liver fibrosis in Schistosoma japonicum[J]. Chinese Journal of Pathogenic Biology, 2017, 12(5): 385-8, 393.

[6] Zhang Ying-Luo, Yin Cai-Ping. Preliminary study on the antibacterial activity of 15 kinds of traditional Chinese medicine extracts against several plant pathogenic fungi [J]. Journal of Northwest A&F University (Natural Science Edition), 2005, 33(S1): 175-7.

[7] Wu Xuefen, Bai Yan. Extraction of medicinal ingredients from honeysuckle leaves and antibacterial test [J]. Traditional Chinese Medicine, 2001, 23(6): 448-449.

[8] Qian Lihong, Tao Yan, Xie Jing. Bacteriostatic mechanism of tea polyphenols against Staphylococcus aureus and Pseudomonas aeruginosa [J].  Microbiology Bulletin, 2010, 37(11): 1628-33.

[9] Fan Jia, Tao Yuwei, Han Xu, et al. Experimental exploration of the antibacterial effect of green tea and its application [J]. Experimental Technology and Management, 2018, 35(6): 190-2.

[10] Zhang Shuai, Zhang Shunwen, Wu Fang, et al. Research on the mechanism of drug resistance of Mycobacterium tuberculosis with mono-isoniazid resistance by ubiquitin-like proteasome system [J]. Chinese Journal of Pathogenic Biology, 2017, 12(6): 489-94.

[11] Shi W. Research on the antibacterial mechanism of effective components of traditional Chinese medicine [J]. Science and Technology Information, 2011 (5): 37, 49.

[12] Xi QP, Tang RY, Wang QF, et al. Study on the antibacterial plaque biofilm effect of gallnut in an artificial oral cavity [J].  Journal of Endodontology and Periodontology, 2004, 14(3): 148-50.

[13] Zhao Yu, Yang Fei, Zhang Xin, et al. Research on the changes in the activity of several redox enzymes in the roots of ginseng during the growing season [J]. Liaoning Journal of Traditional Chinese Medicine, 2012, 39(8): 1586-8.

[14] Liu Di. Research on the synergistic inhibition of ginsenosides on oxidative stress damage in HEK-293 cells and its mechanism [D]. Jilin University, 2016.

[15] Wang Hainan. Advances in pharmacological research on ginsenosides [J].   Chinese Clinical Pharmacology and Therapeutics, 2006, 11(11): 1201-6.

[16] Li Yang, Zhang Tiejun, Liu Suhuang, et al. Research progress on the chemical composition and pharmacological effects of ginseng [J]. Chinese Herbal Medicine, 2009, 40(1): 164-6.

[17] Chen Qun, Liu Jiachang. Research progress on ginseng polysaccharide, astragalus polysaccharide and wolfberry polysaccharide. Journal of Huainan Normal College, 2001, 3(2): 39-41.

[18] Li Zhiping, Yu Xiufang, Hang Hu, et al. Research on the promotion of metabolic processes in Staphylococcus aureus by ginseng [J] . Journal of Physical Chemistry, 1995 , 12(5) : 468-71 .

[19] Cao Junling. The effect of ginsenosides Rg1, Rb1 and Rd on the biological heat activity of Escherichia coli [A] .   Chinese Pharmaceutical Association, Hebei Provincial People's Government. 2008 Annual Meeting of the Chinese Pharmaceutical Association and Proceedings of the 8th China Pharmacist Week [C]. Chinese Pharmaceutical Association, Hebei Provincial People's Government, 2008. 2771-4.

[20] Lin Fengqiang. The immunoadjuvant effect of ginsenosides on the vaccine against Staphylococcus aureus mastitis in dairy cows [D]. Zhejiang University, 2002.

[21] Yu Guodong, Peng Zhiyun. Clinical observation on the treatment of lower respiratory tract infections caused by multi-drug resistant bacteria with Baihu Jiaren Tang [J].  New Chinese Medicine, 2012 ,  44(5) :  31-2 .

[22]    Liu Fangfang, Zhang Aihua, Lei Jingjie, et al. Inhibitory effect and mechanism of ginseng stem and leaf total saponins on Fusarium solani[J] . Journal of Jilin Agricultural University , 2018 ,  40(1) :  85 -91.

[23] Dong Chunlei. Research on the inhibitory effect of ginsenoside monomers and their combined application with other Chinese medicine monomers on bacterial biofilms [D]. Changchun University of Traditional Chinese Medicine, 2011.

[24] Yin Liangjun, Zhou Zhenqi, Shao Yuan, et al. Study on the antibacterial effect of berberine hydrochloride, ginsenoside Rb1, baicalin and chlorogenic acid on Escherichia coli and Staphylococcus aureus [J]. Medical Review, 2016, 22(24): 4969-72.

[25] Liu Jueling, Yang Weifeng, Wang Yi. Research progress on bacterial biofilms and antimicrobial activity of surfactants [J]. Chinese Journal of Pathogenic Biology, 2016, 11(9): 858-60, Appendix 3.

[26]    Lister JL ,  Horswill AR.  Staphylococcusaureus biofilms :  recent developments in biofilm dispersal[J] .  Front Cell Infect Microbial ,  2014(4) :  178.

[27]     McCartby  H ,  Rudkin JK ,  Black  NS ,  et  al.   Methicillin  resistance  and  the  biofilm  phenotype  in  Staphylococcus aureus [J] .  Front Cell Infect Microbial ,  2015(5) :  1.

[28]    Aka ST ,  Haji SH .   Sub-MIC of antibiotic induced biofilm formation of Pseudomonasaeruginosa in the presence of chlorhexidine [J] .  Braz J Microbiol ,  2015 ,  46(1) :  149-54 .

[29] An Jihong, Lü Weiling, Zhang Yongzhou, et al. Effect of ginsenosides on biofilm formation by Staphylococcus aureus [J]. Journal of Shandong University (Health Sciences), 2018, 56(7): 14.

[30]    Zhang J ,  Sun  Y ,  Wang  Y ,   et al.   Non-antibiotic  agent ginsen- oside 20(S) -Rh2enhanced the antibacterial effects of ciprofloxacin invitro and invivo as a poterntial NorAinhibitor[J] .  Eur J Phar- macol ,  2014(740) :  277-84 .