The Potential of Discovering Novel Antimicrobials

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Traditional medicine is based on the traditional knowledge which is held by indigenous cultures. Development of these natural medicines, used to maintain health, was largely due to trail, error, theory and belief processes (World Health Organisation (WHO), 2008). Plants have evidently been used for medicinal purposes for 60,000 years as reviewed by Cowan (1999) and Grossel-Williams et al. (2006) and as natural medicines or dietary supplements in every culture for thousands of years. The 'recipes' for these drugs are described in herbal books or are passed down verbally from generation to generation (Zuo, et al., 2008). An example is the pharmacopoeia of Emperor Shen Nung of China which describes the medicinal uses of Hemp, Aconite and Opium, circa 2800BC (Grossel-Williams et al., 2006). They have been used to fight disease and still play a major role in the developing world (Singhuber et al., 2009). In many Asian and African counties 80% of the population depend on traditional medicines as primary health care (Samy & Ponnampalam, 2008; WHO, 2008), for example they are still prominent as drugs in communities that are poor and live in harsh conditions such as the Hakka peoples living in Guangdong, China (Au, et al., 2008).

A lot of interest has been invested in traditional Chinese medicine (TCM), traditional Indian medicine (TIM) and traditional African medicine (TAM) due to the great potential in both human medicine and veterinarian medicine. It is predicted that the herbal industry already shares about $US 62 billion of the global pharmaceutical market, worth $US 550 billion (Patwardhan, et al., 2005), and is growing by around 5-15% per annum (Joshi et al., 2004). In the USA in 2001, $US 17.8 billion was spent on dietary supplements of which $US 4.2 billion was on herbal medicines; in the UK in 2000 £115 million was spent on complementary medicines, 57% of which was on herbal medicines; in Australia, 2002, estimated expenditure was $AUD2.3 billion; and in Germany expenditure in 1998 was €2 billion as traditional Chinese medicines are very popular in the country, with 66% of the population in favour of them (Dobos, et al., 2005).

Used in modern medicine

Traditional medicines have been, and continue to be used, in the western worlds dietary lifestyle in the forms of supplements, herbs and teas. Teas promote health due to containing polyphenols which aid the probiotic flora in the body, in turn maintaining a healthy gut (Lee, 2006). Efferth, et al. (2008) explains how it is estimated that three-quarters of pharmaceutical drugs are derived from their use in traditional medicines. This is most likely a worldwide average figure as WHO, 2008, estimate 80% of drugs used in Asian and African countries are herbal, while other literature suggests lower use in Western civilisation, with approximately 50% of pharmaceutical drugs derived from botanicals (Cowan, 1999; Treasure, 2005). Very few of these are antimicrobials due to the advances of antibiotics in the 20th century (Cowan, 1999).

Marketed drugs such as artemisinin and capsaicin can be regarded as poster-children of traditional medicines (Corson & Crews, 2007). Artemisinin derived from the herb Artemisia annua and has been used in TCMs for thousands of years and has potent antimalerial activity against multidrug resistant Falciparum malaria (Corson & Crews, 2007; Klayman, 1985). However despite its widespread deployment, issues finding a high yielding synthetic strand, or maintaining plant conditions do make this drug expensive (Corson & Crew, 2007).

Due to complex mechanisms and pathways of chronic pain, treatment drugs are not that effective, have side effects or have safety issues (Immke & Gavva, 2004). Capsaicin, an alkaloid, is found in chilli peppers and gives the pepper its spicy sensation (Corson & Crew, 2007). It has been used as a pain reliever for many centuries in the Americas, and is now topically applied in modern medicine as a pain reliever (Corson & Crew, 2007; Malmberg et al., 2004). Malmberg and colleagues, 2004, developed a patch containing capsaicin which could be applied to the area of pain.

Groups of antimicrobial groups and their structure

Antimicrobial activity has evolved in plants and act as a defence mechanism, a plant oder, to give plant pigmentation or as a plant flavour (Cowen, 1999). Bio-discovery research aims to identify plants that contain novel phytochemicals that may have antibacterial activity (Powell, 2008). Useful antimicrobial phytochemicals can be separated into divided categories (Cowan, 1999; Samy & Gopalakrishnakone, 2008):

Phenolics and Polyphenols

Within this group there are simple phenols and phenolic acids; quinones; flavones, flavoids, and flavonols; tannins; and coumarins (Cowan, 1999). Simple phenols and phenolic acids consist of a single substituted phenolic ring (Cowan, 1999). Quinones are aromatic rings with two ketone substitutions (Cowan, 1999). Flavones are phenolic in structure but contain one carbonyl group (Cowan, 1999). Flavonols are similar to flavones though contain an additional 3-hydroxyl group and flavonoids also contain 3-hydroxyl groups though occur as a C6-C3 unit linked to an aromatic ring (Cowan, 1999). They are ubiquitous in plants and are mainly present in seeds, fruit skin, peel, bark or flowers (Grazul & Budzisz, 2009). Tannins are divided into two groups: hydrolysable and condensed tannins (Cowan, 1999). Hydrolysable are made up of gallic acid as multiple esters with D-glucose, while condensed are derived from monomers of flavonoids (Cowan, 1999). Coumarins are comprised of benzene fused with α-pyrone rings (Grazul & Budzisz, 2009). As this group is so

broad it contains a large range of uses, from antiviral and antibacterial activity (Wong et al., 2008) to antidepressant actives of quinines in St. Johns Wart (Cowan, 1999).

Terpenoids and Essensial Oils.

Essensial Oils are secondary metabolites and are based on an isoprene structure, when they contain additional elements, such as oxygen, they form terpenoids (Cowan, 1999). Terpenoids and essensial oils are responsible for the fragrance of plants (Cowan, 1999) and exhibit antimicrobial, including against S. aureus and Mycobacterium tuberculosis, (Fyfe et al., 1998; Gordien et al., 2009; Mathabe et al., 2008), anti-fungal activity and even anti-antiangiogenic activity (He et al, 2008).


Alkaloids are made up of heterocyclic nitrogen compounds (Cowan, 1999). They naturally occur in seed baring plants, are generally colourless and have a bitter taste (Cordell, 2003). Well known alkaloid include morphine, caffeine and nicotine (Cordell, 2003). Diterpenoid alkaloids, Isolated from the Ranunculaceae family, commonly have antimicrobial activities (Samy & Gopalakrishnakone, 2008).

Lectins and Polypeptides

These proteins are possibly the first line of defence for a plant as they are usually found in cells of the external layers of tissue (Samy & Gopalakrishnakone, 2008). Lectins often exhibit antibacterial activity, for example lectin extracted from seeds of Eugenia uniflora and exhibiting activity against S. auereus, Psuedomonas aeruginosa, Streptococcus sp. and Escherichia coli (Oliveira et al, 2008). Freire et al. (2002) also notes antifungal activity that some lectins possess.

Scientific analysing techniques

A sensible way to start looking for potential phytochemicals is to gain traditional knowledge from the populace which hold such information. A team of investigators travel to places of interest to gather information from the community in the region. Groups can comprise of many skill sets such as ethnopharmacologists, pharmacognosists and botanists, translators and local authorities (Au et al., 2008). Information is then crosschecked with a database before deciding which natural products require further analysis (Au et al., 2008).

Extraction methods

Traditional healers would usually prepare crude plant mixture using boiling water extraction to create a paste, juice, soup, tea (Au et al., 2008; Samy & Gopalakrishnakone, 2008; Singhuber et al., 2009) or a medical bath (Au et al., 2008). These technique extracts phytochemicals into the water and lowers the toxicity of certain drugs, such as Aconitum, which has a high diterpene alkaloid (DDA) content, converting it into the less poisonous monoester diterpene alkaloid (Singhuber et al., 2009).

Initial scientific experimentation follows a similar method. Samples are usually extracted using maceration (liquid-liquid extraction) with a solvent, such as a high concentration of ethanol (Wong et al., 2008; Zuo et al., 2008) or by pressurized hot water extraction (PHWE), at 160ËšC and at high pressure (60 bar) (Deng et al., 2004). Other solvents used, depending on the chemical, include methanol, acetone, steroids, hexane, diethyl ether, chloroform, dichloromethane or ethyl acetate for extraction (Efferth et al., 2008; Samy & Gopalakrishnakone, 2008). The concentrations of liquid or solvent used and in which combination varies to a certain extent in the literature, and when performing experimentation it would be recommended to try a range to ensure high-quality results.

Before or after initial analysis further improved extraction and purification is possible by repeating extraction steps or by coupling them with additional steps such as sonication (Yu et al., 2002; Zuo et al., 2008), HPLC, UPLC (Tang et al., 2009; Yu et al., 2002), MPLC or TLC (Efferth et al., 2008). With the extremely pure compounds attained identification can be completed using nuclear magnetic resonance (NMR). A popular choice of extraction and purification is NMR coupled with ESI-MS (Efferth et al., 2008; Yin et al., 2009).

Screening of antimicrobial activity is performed on model organisms (Wong et al., 2008; Zuo et al., 2008). Agar diffusion with analysis of zone diameter antibacterial activity on agar plates (Zuo et al., 2008) or macrobroth susceptibility test in test tubes are two common techniques (Wong et al., 2008). 96-well microplates are used to find the minimum inhibitory concentration (MIC) (Mathabe et al., 2008).

Alternative techniques are available. Lang et al., 2008, argues the techniques mentioned above are expensive, due to the technology and manpower needed, and results often harbour previously characterised compounds instead of novel ones. Various pieces of literature state the difficulty of identification or discrimination of a particular compound to be a major flaw of methods (Guan & Li, 2010; Joshi et al., 2004; Lang et al., 2008). Lang and his co-workers (2008) demonstrate a new method of 1D and 2D 1H NMR which accelerates the dereplication process (identification of novel compounds) by using a database to phase out recognised, and thus already characterised, compounds early on in experimentation. Another rapid and discriminatory method combines enzyme degradation with chromatography, and with the results more properties can be acquired to tell compounds apart (Guan & Li, 2010).

Molecular Methods

Molecular methods overcome discrimination and misidentification issues, such as a botanitcal having a different name in a different locale (Joshi et al., 2004), as well as offering a very high quality controlled technique. By analysing conserved, unique, DNA polymorphisms they can be used as markers to identify a species (Joshi et al., 2004). Methods to analyse DNA include hybridization-based methods, which probes target restriction fragment length polymorphism (RFLPS); PCR-based methods and sequence-based markers (Joshi et al., 2004). The results can be used to build a complementary DNA (cDNA) library to compare with future findings; any unknowns then found could be analysed to see if they are triggering antimicrobial activity (Zhang et al., 2003).

Unfortunately this cutting edge technology has its shortcomings. It is time consuming and costly to establish a marker for a species due to large range of specimens, varieties and closely related species that need to be examined, overlap of markers needs to be avoided as well as any possible contaminants related to the species (Joshi et al., 2004). It must also be considered that if a different part of a plant is analysed that does not express phytochemical activity the marker will not be discovered (Joshi et al., 2004). This brings the methods back to the initial interviewing and analytical investigation to discover what is active. As Au and co-workers (2008) discovered in Guangdong, China, 39% of medicines contained the whole plant, 21% contained the leaf, 20% contained the root and 20% contained other parts of the plant. It is recommended that both analytical and molecular techniques are used in tandem to gain the best results (Joshi et al., 2004). Such hybrids are becoming more involved such as genome-wide biological response fingerprinting (BioReF), which combines cell culture techniques, identification of a molecular marker using microarrays and qRT-PCR (Rong et al., 2007).

Due to the wide range of techniques there has been a call for some kind of standardisation for quality control purposes (Qiong-lin et al., 2008; Rong et al., 2007; Singhuber et al., 2009). Qiong-lin et al. (2008) went a step further by designing a variable 'road map' which starts from well known recipes of TCMs, through to testing, to databases, to human trials.


As traditional medicine has been used for thousands of years there has been an inadvertent selection process directed towards the medicinals that are most effective (WHO, 2008). With only a small portion of the estimated 310,000 higher plant species tested, there is highly anticipated prospective for natural medicinal products (Powell, 2008). Recent studies have shown traditional medicines exhibit antimicrobial activity (Ji et al, 2007; Tshikalange et al., 2005; Zuo et al., 2008), anticancer activity (Efferth et al., 2008), control of cardiovascular diseases (Lu et al., 2008; Yu et al., 2002), an alternative fuel source potential and pest control activities (Powell, 2008).

A number of recent papers describe the potential of antimicrobial drugs based on traditional medicines. Seed oil analysed from the Mediterranean native Eruca sativa exhibits antimicrobial against a range of bacteria including E. coli, Ps. Aeruginosa and S. aureus (Khoobchandani et al., 2010) Csupor et al. (2010) wounded rats with a branding iron and found extracts from the traditional Hungarian medicinal plant Centaurea sadleriana, when topically applied, increased the speed of wound healing; it is hypothesised this is an antimicrobial effect though it is not verified in the study.

Recent advances in Asia include the stem from the Korean plant Vitis amurensis producing antimicrobial activity against two Streptococcus strains; S. mutans, which is associated with plaque formation, and S. sanguis, which causes subacute bacterial endocarditis (Yim et al., 2010). Two compounds, Piceatannol and trans-É›-Viniferin, were very affective, though the seven other compounds tested did not harbour as impressive, if any result (Yim et al., 2010).

Natural antimicrobials from Africa include the compound Luteolin, a flavonoid, extracted from a range of South African plants which has a potential to cure sexually transmitted disease (Tshinkalange et al., 2005). Mbosso et al. (2010) tested a range of Cameroonian plants for antimicrobial activity. A few to take note of are the fruit extracts from Monodora myristica and ethyl acetate extracts from the bark of Albizia gummifer; they both exhibited activity against Gram positive and Gram negative bacterium (Mbosso et al., 2010). There have been a number of other antimicrobial discoveries in African plants recently, including Tunisian (Khadri et al., 2010) and Tanzanian studies (Yim et al., 2010). With this in mind research of Chinese Traditional Medicines for antimicrobial activity could unearth valuable compounds to be evaluated.

Anti-microbial resistance

With the discovery of penicillin by Flemming in 1928, and its development by Chain and Florey, the antibiotic revolution began. These drugs offered a valuable cure to diseases that plagued mankind for centuries, such as tuberculosis, typhoid fever and infections (Amabile-Cuevas, 2003). Large investments went into antibiotics to help the Second World War efforts, enabling the control of staphylococcal and pneumococcal infections in the military (Alanis, 2005; Madigan & Martinko, 2006). After World War II antibiotics became commercially available and new antibiotics were discovered due to extensive pharmaceutical research and development (Alanis, 2005; Madigan & Martinko, 2006). Broad and inappropriate use of these drugs in medicine, vetting and agriculture quickly resulting in antibiotic resistance (Madigan & Martinko, 2006). In the late 1930s the first cases of antibiotic resistance were recorded involving Staphylococcus aureus developing resistance to sulphonamides and penicillin (Alanis, 2005). Worryingly this was the first of a long line of resistant microbes. When a strain became resistant another antibiotic would be used until it became ineffective. This process was repeated as it was ignorantly believed that antibiotics would continue to be discovered (Amabile-Cuevas, 2003). This led to multidrug resistance in which a bacterium would be resistant to many antibiotics (Amabile-Cuevas, 2003). An example is Neisseria gonorrhoeae, the bacterium which causes gonorrhoea, developing resistance to penicillin in the 1980s (Alanis, 2005; Madigan & Martinko, 2006), and due to using other antibiotics it now displays multidrug resistance including against fluoroquinolone and ciprofloxacin (Tanaka et al., 2004).

Mechanisms of resistance

Antibiotic resistance is generated in two steps; an antibiotic is needed that is capable of killing the majority of the bacterium species in question, and at least one of these microbes has to have the genetics of resistance, leaving the resistant ones to multiply creating a population (Levy & Marshall, 2004). There are two categories for a bacterium to attain resistance; (1) the transfer of genetic information by conjugation, transformation of transduction or (2) through mutations in the bacterial chromosome (Alanis, 2005; Levy & Marshall, 2004). The antibiotic is ineffective due to the expression of the resistant genetic material; with either antibiotic destruction, antibiotic transformation, antibiotic active efflux or receptor modification (Alanis, 2005; Madigan & Martinko, 2006).

Certain microbes are naturally resistant to antibiotics, for example mycoplasmas do not have a cell wall and are not affected by penicillin. Likewise most Gram negative are impermeable to penicillin (Madigan & Martinko, 2006).

Resistance in Human Medicine

Never far from the news is the stories surrounding 'super-bugs' in hospitals due to the misuse of antibiotics (Madigan & Martinko, 2006). Due to the major problem of antibiotic and multi-drug resistance of microorganisms, alternative antidotes are required as the detrimental effects of the likes of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium (VRE) and isolates of Mycobacterium tuberculosis worsen (Madigan & Martinko, 2006). The number of deaths due to MRSA has dropped in the last two years, more than likely due to the tightening of controls on antibiotics, though still around a fifth of hospital infections in the UK are caused by MRSA (around 1200 deaths in 2008) (Office for national statistics, 2009). Furthermore on estimate MRSA costs the UK National Health Service around £1 Billion a year (Cepeda et al., 2005).

Many scientific studies have concentrated on intensive care units. Evidently decreasing the amount of antibiotics used in a hospital can improve their sensitivity to bacteria. In a Greek hospital the usage was decreased by 92.5%, and then a further 55.4% leading to bacterial species more susceptible to antibiotics (Ntagiopoulos et al., 2007). Messadi et al. (2008) found in an intensive care burn unit that the increased usage of the antibiotic ciprofloxacin increased Pseudomonas aeruginosa resistance, conversely the antibiotics ceftazidime, imipenem and amikacin did not influence resistance of Ps aeruginosa. Therefore the case of reducing antibiotics reduces antibiotic resistance is not black and white; another example is that most antibiotic resistance dropped in an Estonian hospital even with an increase in antibiotic consumption: 47.6 defined daily dose (DDD) /100 in 1995 to 62.1 DDD/100 in 1998 (Naaber et al., 2000). However this case is questionable as certain antibiotics have been changed in the hospital, for example new ones included amikacin and imipenem which are more effective against gram negative bacteria (Naaber et al., 2000). Over time there is potential for resistance developing against these drugs too. There is a call for more stringent control over antimicrobials (Naaber et al., 2000; Ntagiopoulos et al., 2007), though no alternative to replace them.

Resistance in Veterinarian Medicine

Resistance is also prevalent in animals. Campylobacter jejuni, a foodborne pathogen, has became resistant to fluoroquinolone due to the over use of the antibiotic to treat poultry flocks (Madigan & Martinko, 2006). Antibiotic drugs have been used on farm animals as antimicrobial growth promoters, continuously added to feed which promotes growth, feed efficacy and decreases waste production (Van den Bogaard & Stobberingh, 2000). There is a fear such practices will lead to residues of the antimicrobials being transferred meat for human consumption (Poucke et al, 2006). Any antimicrobials being used on animals that are similar to ones being used on humans is very dangerous (Wegener, 2003); certain promoters are even analogues of our last line of defence against MRSA (Poucke et al, 2006). Berge et al. (2005) notes an increase in multiple antibiotic resistant E.coli in calves, even when there is a lack of antibiotic pressure. Antibiotic resistance is also present in various other types of farmed animals, for example farmed shrimp and fish. Tendencia & de la Peña, 2001, show resistant bacteria levels where considerably higher in pools in which antibiotics where administered. Chelossi et al (2003) also links antibiotic usage to antibiotic resistance, with 96% of bacterium, 73 gram-possitive and 26 gram-negative, resistant to at least one antibiotic, including streptomycin and ampicillin, in fish farms in the Western Mediterranean.

In addition concerns have been raised on hospital and agricultural waste containing antibiotics filters into the surrounding environment. This affects the bacterial community on a whole, and potentially could majorly disrupt the ecosystem, and harbours a sink for dangerous human pathogens (Chelossi et al., 2003; Martinez, 2009). Traditional medicines offer an alternative to antibiotics in the form of natural antimicrobials. Furthermore antimicrobials could be used to tackle bacterial infections in which there are currently no approved drug for, for example Johne's dieases (Wong et al., 2008), prevention against food spoilage and as an alternative drug against non-resistant bacteria in health and agriculture.

Regulation and effects

Alternative preventive methods in the form of laws are being used to stop the spread of drug resistance. As a preventative measure the European Union banned certain antibiotic growth promoters (AGP); Zinc bacitracin, spiramycin, tylosin and virginiamycin under the Commission Regulation 2821/98 and olaquindox under the Commission Regulation 2788/98 (Poucke, et al., 2004; Poucke, et al, 2006). Concern is still mounting as investigation shows a lack of stringency in use of antimicrobials in animals; differences in the expected and observed levels of antibiotics continue and with a lack of homogeneity (Poucke, et al., 2006).

Unfortunately with the thoughts of animal and human welfare in mind there have been some negative effects of banning AGPs. When AGPs were phased out in Sweden and Denmark the amount of therapeutic antimicrobials greatly increased in the first two years. Levels dropped again with a decline in Denmark of 36% from 1996 to 2003 (Grave et al., 2006). This could be due to an increased susceptibility to disease after dependency on antibiotics, or due to rising and improved monitoring techniques preventing illegal use of therapeutic antimicrobials as AGPs. Grove, et al. (2006) explains in the long run the ban has reduced the use of antimicrobials in Denmark, Norway and Sweden. Wegener (2003) clarifies there has been no major effects in terms of feed efficiency or productivity, and the positives of reducing the chances of antibiotic resistance outweigh negative impacts. One well documented exception however is the weaner pigs which declined in daily weight gain from 422g in 1995 (before regulation) to 415g per day in 2001 (after regulation) (Dibner & Richards, 2005; Wegener, 2003).

A natural alternative, with a low prospect of resistance, and which could eradicate the need for antibiotics could entice nations, such as the USA that are not banning AGPs, to change their stance point.

The regulatory status of traditional medicines for human consumption varies in each country. In the USA most herbal drugs are sold as "dietary supplements" which do not require a prescription, though there are some exceptions; the UK is similar though with more prescription only drugs; in Germany all are prescription only; and in Australia they are sold as "therapeutic goods" (Dobos et al., 2005). Each new drug or supplement requires a good manufacturing process (GMP) and have to pass a quality control (QC) system as a requirement to obtain the ability to be sold (Dobos, et al., 2005).

Traditional Chinese Medicine

TCM was developed alongside one of the oldest traditions in the world today, and so in theory the most useful natural drugs have surpassed the test of time. From this a large number of herbal formulations are available from the classical Chinese pharmacopoeia (Yuan & Lin, 2000). However it does not automatically mean that the ancient medicines are useful as Ramsey (2006) poetically relates the lengthy presence of traditional medicines to the lengthy presence of astrology, and how it does not stand up to scientific scrutiny. Still through scientific experimentation actives have been found in these medicines, including antimicrobial ones.

As stated there has not been a large amount of investigation into antimicrobial activity of TCMs however some there are positive results. Eriocaulon buergerianum, used in TCM as an ophthalmic, anti-inflammatory and antimicrobial, and Aquilegia oxysepala, used in TCM to treat gynopathic disease, both TCMs proved effective against S. aureus (Fang et al., 2008; Yu et al., 2006). Cinnamon oil, which is 85% cinnamaldehyde, from the herb Cinnamonum cassia has an impressive array of antimicrobial activity against not only S. aureus but against a host of bacteria including E. coli, Ps. Aeraeruginosa, salmonella typhymurium and Enterobacter aerogenes, all Gram negative bacteria (not including S. auerus) (Ooi et al., 2006).

With review of the scientific literature no single species or compound has been analysed repeatedly for anti-MRSA activity, though species from the plant Families Labiatae and Polygonaceae have been repeatedly used, instead thus far a range has been investigated with promising activity (TABLE #). Some notable examples with anti-MRSA activity include impressive minimum inhibitory concentrations (MIC) such as from the essential oil of Ganoderma japonicum (MIC: 1.03mg/ml) (Liu et al., 2009), Dendrobenthamia capitata (MIC: 1.25mg/ml), Elsholtzia rugulosa (MIC: 1.43mg/ml), Elsholtzia blanda (MIC: 1.32mg/ml), Geranium strictipes (MIC: 1.34mg/ml) and Polygonum multiforum (MIC: 1.34mg/ml) (Zuo et al., 2008). These antimicrobial affects are humbled by fractionated and purified samples; in the same experimentation Zuo and his co-workers (2008) fractionated betulinic acid from the leaves of Dendrobenthamia capitata and when tested its MIC was an impressive 62.5µg/ml. Similarly Chalcomoracin was fractionated from Morus alba proving very effective against MRSA with a MIC of 0.78µg/ml (Fukai et al., 2005). This impressive functionality of fractionated compounds is contradictory to literature that states TCMs work so well due to the nature of a mixture of herbs rather than one to one drug targeting and treatments (Chiang, 2000).

Synergistic activity also has promise against MRSA strains. When combined with antibiotics results show an improvement. Isatis tinctoria and Rheum palmatum combined with the antibiotic ceftrianxone had an MIC of 4.6µg/ml and 4.2µg/ml consecutively and Scutellaria baicalensis combined with ciprofloxacin had a MIC of 2.4µg/ml (Yang et al., 2005). A study combined fractionation with antibiotic syngergy: baicalin extracted from Scutellaria amoena had a MIC of 64µg/ml, though when combined with an antibiotic results ranged from 4µg/ml-16µg/ml [Combined with Cefotoxamine: 4µg/ml, Methicillin: 4µg/ml, Ampicillin: 8µg/ml, Benzylpenicillin: 16µg/ml] (Liu et al., 2000). Experimentation with samples is needed to discover which delivery option is best, though fractionation, synergy with an antibiotic, or a combination of the two seems more effective than raw extract. Literature reports initial success against other resistant species, for example penicillin-resistant S. aureus (Liu et al., 2000), Methicillin-senstive S. aureus and S. saprophyticus (Liu et al., 2009).

Some studies which have applied antimicrobial activity to other diseases and problems. TCM antimicrobials have a huge potential to replace banned antibiotics in farm feeds or as food additives (Wong et al., 2008). Extracts from the Chinese herb Eupatorium lindleyanum have potential to prevent food spoilage as it presents activity against a host of organisms, and it would only have to be used in small doses (Ji et al., 2007). Certain species from the family of plants Apiaceae are used in TCM (Li et al, 2005) and antibacterial activity has been analysed against pathogens using plants from the same family, though species not used in TCM (Oroojalian et al, 2010). As not many studies have been conducted, sources outside TCM can demonstrate the principles and potential.

There are even fewer studies on using antimicrobial TCM for veterinarian use, again principle applies. Evidently herbal medicine can cure animal based disease as Wong et al., 2008, tested 18 compounds against Mycobacterium avium subsp. Paratuberculosis (MAP), which causes paratuberculosis in cattle and currently has no approved cure. Six compounds inhibited the growth of MAP. The most successful were trans-cinnamaldehyde with a MIC of 25.9 µg/ml, and cinnamon oil with a MIC of 26.2µg/ml (Wong et al., 2008).

Most of the investigations are based on traditional knowledge, and are initial studies, which are important to find if a natural product possesses antimicrobial activity, though more advanced studies are needed into plants with proven activity and into specific compounds with activity (Zuo et al., 2008).

Advantages and Disadvantages

The public perception may be that traditional medicines, rather than chemical medicines, would be viewed as a natural and healthier alternative (Fyfe et al., 1998), though scientific peer assessed literature and rigorous testing are evidently needed. Ramsey (2006) believes the toughest task for herbal medicine is it is overhyped, and the herbal literature is full of inaccuracies and finding and developing a mainstream pharmaceutical from a crude plant mixture is a daunting task. This is evident in Efferth and co-workers (2008) study as they discovered that certain compounds from the flowering plants Quisqualis indica and Salvia miltiorrhiza had anti-tumour effects, while conversely its use in traditional Chinese medicine is for heart disease, inflammation, and menstrual disorders. On the other hand Efferth et al. (2008) actually see this as promising rather than a setback, taking the view that this shows traditional medicine has an even greater and wider potential than previously thought.

Ironically the 'natural' compound may have to be synthesised by pharmaceutical companies as it could be a quicker and cheaper process, which also enables up-scaling of production, without the maintenance of plants. However due to the complexity, which makes the phytochemicals so successful in the first place, it difficult for synthetic chemists to create a product with the intended natural biological activity (Corson & Crews, 2007). Pharmaceutical companies are concerned with patentability of natural products, synthesizing, even though it is a difficult task, may be the only possible way to gain a patent (Johnston, 2005). Huang and his colleagues in 2001 synthesised β-adrenoceptor blockers (vanilloid) based on traditional Chinese herbal medicines, the synthesised drugs all exhibited β-adrenoceptor blocking activity. Raskin et al. (2002) discussed how it is important to take the natural phytochemical and test various synthesised homologs to see which is the most functional, as Huang et al. (2001) performed. It may be recommended that some focus is put on testing synthetic forms of natural products found, and collaboration between biologists and chemists to ensure no vital information is missed, as Huang et al. (2001) unfortunately did not record what herbs were used in the study.

This review advertises how many traditional medicines have antimicrobial effects, though some microbes also have natural defence mechanisms. Biofilms can make antimicrobials ineffective as they cannot bypass the protective layer, however this would not be the end of the line for traditional medicine, as Lu et al. (2007) explains that the bacteria in dairy cow mastitis, which develop a biofilm, can be removed using herbs which increase blood flow. Just to note a few papers shed a concern about a stronger effect of antimicrobials on Gram positive than Gram negative bacteria, though there is still effective doses against such strains (Ji et al., 2007; Wong et al., 2008).

In modern day medicine many treatments are centralised around a single compound, such as an antibiotic, to battle an infection or disease. Traditional medicines offer a group of substances against disease or infection (Qiong-lin et al., 2008) and therefore lessen the chance of resistance. Efferth et al., 2008, states the urgent need for a natural alternative which would remove the involvement of multidrug resistance.

Investigation has shown great potential for synergism, where a traditional medicine interacts with another factor to exalt a greater effect, commonly herb-herb interactions. Other odd finds include wogonin synergising with the cytokine TNFα, which then causes apoptosis specifically in cancer cells by interfering with the antiapoptic stress response (Daniel, 2006). Fyfe et al., 1998, demonstrated how synergy between the oil (from fennel), anise or basil with either benzoic acid (more effective) or methyl-paraben (less effective) has great antimicrobial effect against the food borne pathogens Listeria monocytogenes and Salmonella enteriditis. This synergism drug use further decreases any likelihood of microbial resistance to natural drugs (Fyfe, et al., 1998). The author admits the administration could affect the taste of the food it is preserving, though the combinations are so effective only low concentrations are needed.

On the other hand mixing certain medicines can have adverse effects, for example Aconitum and Cyrrhiza inflata causes their main ingredients to react if not prepared in the correct concentrations (Singhuber, et al., 2009). However modern science has defied traditional medicinal knowledge by finding contrasting results about certain substances which were believed not to mix well; a key example Aconitum and Pinellia ternate which actually reduces the toxicity of Radiz Aconiti (Liu et al., 2008 IN Singhuber, et al., 2009).


With particular interest surrounding antibiotic and multidrug resistance, plus laws forbidding the use of antibiotics on animals, there is a demand in the Western world for a new potential cure for human and veterinarian ailments. Potential presents itself in the form of traditional medicines, in particular antibacterial components in traditional Chinese medicine (TCM). However this foresight is not without its drawbacks and implications.

Potentially any natural substance could harbour antimicrobial activity; traditional medicine is a good starting point for research. It has been seen to work for particular indigenous people and now some medicines have been proven to have activity through scientific research. Indeed any traditional medicine sector could be chosen, and harbour effects, though TCM offers a smaller, though vast, portion of natural products to examine and being one of the oldest traditions it should have a high concentration of actives.

In a similar sense any scientific discoveries need to tested in various ways as this could affect activity. The most active could be in its crude form, part of a synergism, in a refined, fractionated and pure form, or due to another factor not yet discovered.

It is important that the 'bottomless pit mentality' of antibiotics is not adopted as the future is not known, and as Ramsey (2006) states it has to be scientific, without any superstitious or supernatural perspective. With that in mind there is huge prospective for finding a new preventive for MRSA, and other antibiotic resistant drugs, along with replacements for antibiotics in human and in veterinarian medicine. With the evidence from Chinese botanicals, and botanicals from around the globe, TCM is an untapped source of antimicrobials awaiting to be discovered.