Multi-Drug Resistant Bacteria

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Background

Multi-drug resistant bacteria emerge as a result of inappropriate use of antibiotics and pose serious threats to human health. There is a need for novel drugs to address this problem, which is a huge challenge for the development of novel and efficient antibacterial agents. Tannins are high molecular weight polyphenols (500?30,000 Da), widely distributed among plant kingdom. Tannins are one of the major components in many traditional medicinal plants with potential health benefits and wide applications in leather and food industries.

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Hydrolyzable tannins made up of the esters of gallic or ellagic acid and glucose, and condensed tannins also known as proanthocyanidins, the polymers of catechins or epicatechins, are two major groups of tannins. Recent studies indicate that tannins are natural compounds with remarkable antibacterial activity.

Scope and Approach

The present review addresses the classification of tannins and their antibacterial effects targeting bacterial growth and virulence factors, and highlights the underlying antibacterial mechanisms of action. Furthermore, an overview of the antibacterial effects of emerging tannin-based nanoparticles and hydrogels is presented.

Key Findings and Conclusions

Tannins have been found to inhibit the growth of different bacteria, involving in different mechanisms of action, including iron chelation, inhibition of cell wall synthesis, disruption of the cell membrane, and inhibition of fatty acid biosynthetic pathway. Additionally, tannins can act as virulence inhibitors by inhibiting several virulence factors such as biofilm, enzymes, adhesins, motility, and quorum sensing. Tannin-based nanoparticles and hydrogels exhibit excellent antibacterial effects. However, there have been very few studies on their in vivo therapeutic potentials as antibacterial agents.

Therefore, further in vivo and clinical trials are required to confirm their antibacterial efficacy.

Keywords: tannins; antibacterial; tannic acid; nanoparticle; hydrogel

Introduction

Antibiotics are widely used to treat infectious diseases caused by microorganisms especially bacteria. The use of antibiotics is widespread across the globe. Apart from their clinical use, antibiotics are widely applied in different industries such as agriculture, aquaculture, and livestock farming. The abuse and overuse of antibiotics have led to the emergence of multidrug-resistant bacteria. Most of the antibiotics, which are currently in use, are inadequate to eradicate the bacterial infection due to their resistance to antibiotics. The resistance to existing antibiotics is a growing concern in the health care industry. In this context, there is a need for new antibacterial agents to treat bacterial infections caused by pathogenic bacteria, especially multidrug-resistant bacteria. Natural products from plants are considered as effective antimicrobial agents since they are less toxic to humans and animals. Therefore, the search for antimicrobial agents from plants has received a great deal of attention in recent years.

Tannins are polyphenolic compounds found in an array of plant species with molecular weights ranging from 500 to 30,000 Da (Serrano, Puupponen-Pimi?, Dauer, Aura, & Saura-Calixto, 2009). Tannins are found in diverse plants, especially in many plant-based foods. Mimosa, chestnut, quebracho, maple tree, acacia, oak, and eucalyptus are known tannin-rich plants. In addition, fruits including persimmons, cranberries, blackberries, and grapes are the main sources of food tannins. In unripened fruits, the amount of tannin is comparatively high and its presence protects the fruits from fruit-eating animals before maturation. Tannins are also present in beverages such as tea, coffee, and wine.

Tannins play a major role in plant defense mechanism and protect the plants from predators such as insect and herbivores. Furthermore, tannins involve in the regulation of the growth of plants. Tannins can form insoluble complexes when binding with protein or other macromolecules. Since ancient time, tannins have been successfully used in leather and wine industry (Al-Zoreky, 2009). There are several reports on the use of tannin-rich extracts in traditional medicinal preparations for the treatment of various ailments including bacterial infection (Bhalodia & Shukla, 2011).

Recent studies have indicated that tannins exhibit good antibacterial effects. To provide updated progress on this research field, we have searched related research articles in the database of Web of Science Core Collection for the last ten years, and mainly summarize and discuss the effects of tannins on the bacterial growth and virulence factors, as well as potential mechanisms of action. Besides, the antibacterial properties of tannin-based nanoparticles and hydrogels are also summarized. We hope that this updated review can attract more attention to the antibacterial potential of tannins, and can promote their applications as natural antibacterial agents in the food system as well as clinical infection treatment.

Chemistry and classification of tannins

As naturally occurring polyphenols, tannins are abundant in plants with diverse chemical structures and properties. Based on their structures and properties, tannins can be mainly classified into two groups, hydrolyzable tannins (HTs) and condensed tannins (CTs) or proanthocyanidins. Overall, CTs are more abundant in plants compared to HTs, and most CTs have higher molecular weights (1000?30,000 Da) than HTs (500?3000 Da).

HTs, as the names indicate, can be easily hydrolyzed into monomers by acid, alkali, or enzymatic treatments. HTs are composed of esters of phenolic acids and a polyol, usually glucose. Gallotannins and ellagitannins are the two subclasses of hydrolyzable tannins. In gallotannins, the central glucose molecule is surrounded by several gallic acid units and further gallic acid units are linked through depside bond. Ellagitannins are characterized by the presence of 3,4,5,3?,4?,5?-hexahydroxydiphenoyl (HHDP) moiety, which is formed by the linkage between galloyl units via oxidation reaction.

CTs are mainly composed of flavanoid units (flavan-3-ol) linked by carbon-carbon bonds and are highly complex in nature. Generally, CTs are oligomers/polymers of epicatechin or catechin. The carbon-carbon linkage in CTs is highly stable and resistant to degradation. Hence, CTs are resistant to acid hydrolysis. Treatment with strong acids is necessary to break down the CTs. The number of monomeric subunits and position of hydroxylation of the B-ring of the flavan-3-ol monomer are the main factors that determine the chemical nature and biological properties of CTs. Proanthocyanidins can be divided into different subgroups. A-type proanthocyanidins contain double linkages, including one C-C and one C-O linkages, while B-type (dimeric) and C-type (trimeric) proanthocyanidins are mainly based on the interflavanol linkages formed between the C4 of one flavanol unit and the C6 or C8 of another flavanol unit. Procyanidin is the simplest form of CTs. Fig. 1 shows the chemical structure of representative tannins.

Growth inhibitory effects of tannins

As a defense molecule that protects the plants from pathogens and insects, tannin plays an important role in plant growth. Tannins have been reported to inhibit the growth of diverse microbes, such as bacteria, fungi, and yeasts (Scalbert, 1991), and there has been some new progress in recent years (Table 2).

Tannins can inhibit the growth of both Gram-positive and Gram-negative bacteria. Gram-positive pathogens, including Brochothrix thermosphacta, Staphylococcus aureus, Methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus warneri, Staphylococcus epidermidis, Streptococcus pyogenes, Streptococcus faecalis, Streptococcus pneumonia, Streptococcus bovis, Listeria monocytogenes, Listeria innocua, Enterococcus faecalis, Enterococcus faecium, Clostridium esterthearum, Clostridium cellulosolvens, Clostridium clostridiiforme, Clostridium paraputrificum, Clostridium perfringens, Butyrivibrio fibrisolvens, Bacillus subtilis, Bacillus cereus, Bacillus amyloliquefaciens, Micrococcus luteus, Propionibacterium acnes, Anaerococcus sp. A20, Corynebacterium xerosis, as well as Gram-negative pathogens, including Hafnia alvei, Shewanella putrefaciens, Pseudomonas fluorescens, Pseudomonas aeruginosa, Pseudomonas syringae, Photobacterium phosphoreum, Serratia liquefaciens, Serratia proteomaculans, Rahnella aquatilis, Escherichia coli O157:H7, Enterohemorrhagic E. coli, Enteroinvasive E. coli, Enterotoxigenic E. coli, Yersinia enterocolitica, Klebsiella oxytoca, Klebsiella aerogenes, Klebsiella pneumoniae, Enterobacter cloacae, Enterobacter aerogenes, Alcaligenes faecalis, Proteus vulgaris, Proteus mirabilis, Salmonella enterica, Salmonella enteriditis, Salmonella typhimurium, Salmonella paratyphi, Salmonella arizonae, Salmonella anatum, Shigella flexneri, Cellvibrio fulvus, Sporocytophaga myxococcoides, Vibrio cholera, Vibrio parahaemolyticus, Vibrio vulnificus, Campylobacter jejuni, Helicobacter pylori, Porphyromonas gingivalis, Prevotella intermedia, Aggregatibacter actinomycetemcomitans, Actinobacillus actinomycetemcomitans, Acinetobacter baumannii, Erwinia carotovora, Acidovorax avenae subsp.cattleyae, Burkholderia glumae, Pseudomonas syringae pv.actinidiae, Xanthomonas arboricola pv.pruni, Ralstonia solanacearum, Aeromonas salmonicida, and Bacteroides fragilis, have been reported to be sensitive to tannins. Most tannins have shown bacteriostatic activity (Boakye, Agyare, & Hensel, 2016). Table 1 highlights the growth inhibitory effects of different classes of tannins.

Generally, tannins can either kill the bacteria (bactericidal) or retard their growth (bacteriostatic). The minimum inhibitory concentrations (MICs) of different types of tannins are found in the range of 61.5-3200 ?g/mL. The MIC values of tannins are much lower against Gram-positive bacteria compared to Gram-negative bacteria, which might be due to the structural differences of cell membrane between them. The MIC values tested against bacteria are much lower for HTs, such as tannic acid, corilagin, geraniin, and chebulinic acid, compared to CTs. Among them, tannic acid exhibits the lowest MIC values and is the most studied tannin with broad spectrum antibacterial activities (Chung, Lu, & Chou, 1998).

Tannic acid has shown higher inhibitory activity against Gram-positive bacteria, especially S. aureus, than against Gram-negative bacteria, which are susceptible to tannic acid at concentrations ranging between 0.16-10.6 mg/mL. The discrepancies of the MIC values of tannic acid against the same bacterial species in different studies might be due to the selection of culture medium and bacterial count used for the study. As a natural product, tannic acid is classified as one of the 'generally recognized as safe' (GRAS) food additives. Up to 400 ppm (approximately 0.4 mg/mL) concentration, tannic acid is safe to be applied in food systems. Geraniin exhibits bacterial inhibitory activity at concentrations ranging from 2.5 to 10 mg/mL against Gram-positive and Gram-negative bacteria (Boakye et al., 2016). Hepta-O-galloylglucose ranging from 0.2-2.8 g/L shows significant bacterial inhibitory activity and Clostridium botulinum is found to be more sensitive to hepta-O-galloylglucose (Engels, Schieber, & G?nzle, 2011).

The tannin-rich extracts have been reported to show bacterial inhibitory effects against a wide variety of bacterial pathogens including food-borne bacteria and clinically important bacteria. For instance, gallotannins from Caesalpinia spinosa show MIC values ranging from 0.56 to 50 mg gallic acid equivalent (GAE)/mL. Grape seed extracts rich in proanthocyanidins have bacterial inhibitory activities against different strains of L. monocytogenes, with MIC values ranging from 50-78 ?g/mL (Bisha, Weinsetel, Brehm-Stecher, & Mendonca, 2010).

However, very few types of tannin-rich extracts exhibit bactericidal activity. Chestnut and mimosa tannin extracts are two commercially available tannin extracts, rich in HTs and CTs, respectively. Min, Pinchak, Anderson, & Callaway (2007) reported that tannins from chestnut and mimosa extracts show inhibitory effects on fecal pathogenic bacterial strain E. coli 0157: H7. The bacterial inhibition of tannin-rich extracts, however, varies due to the chemical nature of tannins present in the extract. For instance, mimosa tannins exhibit bacteriostatic activity, while chestnut tannins show bactericidal activity. Anderson et al. (2012) reported the inhibitory effects of chestnut and mimosa tannin extracts against C. jejuni, a causative agent of foodborne illness. Though chestnut tannins and mimosa tannins exhibit bactericidal activity against C. jejuni, chestnut tannin extract is more effective than mimosa extract as an antibacterial agent (Anderson et al., 2012).

Similarly, chestnut tannins show bactericidal activity against C. perfringens (Elizondo, Mercado, Rabinovitz, & Fernandez-Miyakawa, 2010). Gallotannins from Mangifera indica L., show bactericidal activity against foodborne bacteria in the concentration range of 0.2-3.3 g/L (Engels, Schieber, & G?nzle, 2011). Wang et al. (2013) reported that CTs from purple prairie clover is bacteriostatic rather than bactericidal against E. coli O157: H7, a major causative agent of foodborne illnesses. Proanthocyanidins from Acacia mearnsii (Black wattle) exhibit bactericidal effects against E. coli BW13711 under the aerobic condition at high concentrations of tannins (0.2% wattle tannins) (Smith, Imlay, & Mackie, 2003). CTs are auto-oxidized and produce hydrogen peroxide, which inhibits the growth of bacteria. Proanthocyanidins from Cinnamomum zeylanicum display bactericidal effects against L. monocytogenes at a concentration of 0.0083 g/mL (Ostroschi et al., 2018). It should be noted that the concentration of tannin compounds required to elicit antimicrobial effects is much lower than that of tannin-rich herbal extracts.

Lactic acid bacteria (LAB), such as Lactococcus lactis and acid-fast bacteria Mycobacterium smegmatis, exhibit lower susceptibilities to tannins. For Lactobacillus acidophilus ATCC 4356 and Bifidobacterium infantis ATCC 15697, tannic acid exhibits MIC values > 500 ?g/mL (Chung, Lu, & Chou, 1998). Our recent studies also found that Padang cassia, Chinese cassia, and pomegranate peel are rich in tannins, and these spice and medicinal plant extracts (100 mg/mL, 20 ?L) don't inhibit the growth of LAB, including L. acidophilus, Lactobacillus bulgaricus, Lactobacillus casei, Lactobacillus plantarum, and Lactobacillus rhamnosus (Chan, Gan, & Corke, 2016; Chan, Gan, Shah, & Corke, 2018a).

Also, adding tannin-rich pomegranate peel extract no more than 2% (w/v) doesn't affect the viable LAB number in L. acidophilus-fermented milk compared to the control without pomegranate peel extract. Iron chelation is an important bacterial inhibitory mechanism of tannins against many pathogenic bacteria, but iron is not necessary for the growth of LAB since they lack heme enzymes, which is replaced by adenosylcobalamin. This might be the reason for higher MIC values of tannic acid and tannin-rich plant extracts against LAB compared to most pathogenic bacteria (Chung, Lu, & Chou, 1998; Chan, Gan, Shah, & Corke, 2018a). Overall, tannins possess bacterial inhibitory effects against diverse pathogenic bacteria, but are less effective against probiotic bacteria, such as LAB.

Bacterial inhibitory mechanisms of tannins

Iron-chelating activity

Iron is an essential component for the optimal growth of most bacteria. Siderophores, low molecular weight iron-chelating agents produced by bacteria, can help to bind and solubilize iron in the environment and make it available to bacteria. Tannins can chelate iron from media and surroundings, and abrogate its availability to bacteria, leading to the inhibition of bacterial growth due to iron deprivation. The o-dihydroxyphenyl groups in tannin molecules are mainly responsible for the chelation of ferric ions (Slabbert, 1992). Within the tannin molecule, o-dihydroxyphenyl groups can bind with several ferric ions and each ferric ion can itself coordinate with up to three o-dihydroxyphenyl moieties belonging to different polyphenolic molecules. Subsequently, a lattice can be formed, leading to the precipitation of iron along with tannins.

Chung, Lu, & Chou (1998) reported that tannic acid can chelate iron in the environment, making it unavailable for the microbes, and supplement of an additional dose of iron restores the growth of E. coli, which can be inhibited by tannic acid. Tannic acid has high iron-binding efficiency compared to natural siderophores. Iron complexation by gallotannins inhibits the growth of C. botulinum (Engels et al., 2011). The bacterial inhibitory activity of gallotannins isolated from Mangifera indica L. is also attributed to the iron-chelating property of gallotannins. 2, 6-tri-O-galloyl-?-D-glucopyranose, a gallotannin from Terminalia chebula fruits inhibits the growth of multidrug-resistant uropathogenic bacteria by its strong iron-chelating property (Bag, Bhattacharyya, & Chattopadhyay, 2013).

Our recent study also found that gallotannin-rich extracts from the red sword bean coats can inhibit the growth of both Gram-positive and Gram-negative bacteria, most probably associated with the iron-chelating property of gallotannins (Gan et al., 2018). The iron-chelating efficiency of gallotannins is correlated with the number of galloyl groups in the molecule, with a larger capacity at lower degrees of galloylation, and the increase in higher degrees of galloylation has a less iron-binding capacity because of the steric effects (Engels et al., 2010 and 2011). Also, the degree of galloylation does not significantly influence or correlate with the antibacterial activity of gallotannins.