Эпигаллокатехин egcg лечебные эффекты Кожные болезни Сахарный диабет Ожирение Научные исследования Укрепления здоровья эффекты зеленого чая

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EGCG against streptococci and other gram-positive bacteria

Certain Streptococcus species are responsible for many cases of meningitis, pneumonia, endocarditis, erysipelas and necrotizing fasciitis. However, many streptococcal species are non-pathogenic, and part of the commensal human microbiome of the mouth, skin, intestine and upper respiratory tract.

Despite the complexity of oral flora, oral streptococci, including S. mutans, have generally been considered the primary aetiological agents of dental caries (Beighton, 2005). In several studies, it was shown that tea catechins possess antimicrobial effects against oral streptococci. The prevention and a reduction in the formation of dental caries was demonstrated in animal models as well as clinical trials. As the focus of this review is summarizing the spectrum of EGCG activity, we would like to refer the reader to Taylor et al. (2005) who reviewed the anticariogenic activity of EGCG and its effects on periodontal disease.

Streptococcus pyogenes has several virulent factors, including cell surface components (lipoteichoic acid, hyaluronic acid capsule, M proteins, laminin and collagen binding proteins), which are responsible for bacterial adhesion to human cells. EGCG was able to inhibit the attachment of bacteria to pre- and post-treated cells and induce S. pyogenes cell death (Hull Vance et al., 2011). It was concluded that EGCG could be used effectively as an adjunct to conventional antibiotic treatment. However, future studies are needed to elucidate the activity of EGCG against S. pyogenes in animal models. At present, no data exist concerning the antibacterial activity of EGCG against Streptococcus pneumoniae.

EGCG against gram-negative bacteria

It was supposed that gram-positive bacteria are more susceptible to EGCG than gram-negative bacteria (Yoda et al., 2004) because one mode of action of EGCG is to bind to peptidoglucan. The peptidoglucan of gram-negative bacteria is shielded by an outer membrane, that is mainly composed of negatively charged lipopolysaccharides. For that reason it was hypothesized that the physiological function of the outer membrane and low affinity of the also negatively charged EGCG for the bacterial cell membrane would reduce the antibacterial activity of EGCG against gram-negative bacteria (Yoda et al., 2004).

The gram-negative non-fermentative bacillus Stenotrophomonas maltophilia is intrinsically resistant to β-lactams and other broad-spectrum antibiotics and has emerged globally as an important nosocomial pathogen (Brooke, 2012). Two studies have shown that EGCG exerts antibacterial effects against S. maltophilia (Navarro-Martinez et al., 2005; Gordon and Wareham, 2010). Furthermore, it was demonstrated that EGCG is an effective inhibitor of S. maltophilia dihydrofolate reductase (DHFR), and acts synergistically with sulfamethoxazole, a drug that blocks folic acid metabolism (Navarro-Martinez et al., 2005). This type of inhibition is similar to that of trimethoprim. Therefore, EGCG could represent an effective alternative to trimethoprim to combine with sulfamethoxazole for treating S. maltophilia infections especially in strains resistant to trimethoprim. The range of the MIC of EGCG for S. maltophilia is similar to that for Acinetobacter baumannii, another multi-drug resistant pathogen that causes nosocomial infections (Osterburg et al., 2009).

It has been reported that the tea catechins have antibacterial activity against various foodborne pathogenic gram-negative bacteria, including Helicobacter pylori, enterohaemorrhagic Escherichia coli (EHEC), Vibrio cholera, Bacillus spp., Clostridium spp. Shigella spp. and Salmonella spp. (Ryu, 1980; Shetty et al., 1994; Mabe et al., 1999; Sugita-Konishi et al., 1999; Sakanaka et al., 2000; Yanagawa et al., 2003; Taguri et al., 2004; Friedman et al., 2006; Lee et al., 2009; Stoicov et al., 2009). An overview of the existing studies analysing the antimicrobial effects of EGCG against bacteria causing foodborne disease is shown in Table 2.

H. pylori has been identified as an aetiological agent involved in the development of gastric ulcers, peptic ulcers, gastritis and many other stomach-related diseases. Different in vitro and in vivo studies explored the activity of tea catechins against H. pylori. EGCG was the most potent catechin as the MIC values for 50% of the tested H. pylori strains were 8 μg mL−1 (Mabe et al., 1999). Additive effects were shown when it was administered in combination with amoxicillin, metronidazole and clarithromycin, antibiotics usually used as a first line of treatment for H. pylori infections (Mabe et al., 1999; Yanagawa et al., 2003). However, the bactericidal EGCG activity is limited at pH ≤5.0. Also, in infected Mongolian gerbils, H. pylori was only eradicated in 10–36% of the catechin-treated animals (Mabe et al., 1999). It is possible that the pH dependency of the antibacterial activity of EGCG or the short gastric transit time of the agent was causative for the low eradication rate observed in this study. Thus, further studies are needed to assess the efficacy of EGCG in combination with a proton pump inhibitor and a drug delivery system with prolonged gastric transit time (Mabe et al., 1999). Green tea also has prophylactic properties, as it can prevent gastric mucosal inflammation in animals if ingested prior to exposure to H. pylori (Takabayashi et al., 2004; Stoicov et al., 2009).

Shiga toxin-producing E. coli is an important pathogen causing haemolytic-uraemic syndrome, including the EHEC O104 : H4 outbreak in Germany in 2011 where 3816 patients were affected (Frank et al., 2011). Even though the MICs of EGCG against E. coli 0157 : H7 were quite high (539 ± 22 μg mL−1), it was demonstrated that low concentrations EGCG can inhibit the extracellular release of Shiga toxin and decrease quorum-sensing regulated genes, biofilm formation and swarm motility (Okubo et al., 1998; Sugita-Konishi et al., 1999; Lee et al., 2009). In addition, it was observed that infected gnotobiotic mice fed with green tea extracts had significantly lower Shiga toxin levels than the untreated control group (Isogai et al., 1998). The untreated controls developed neurological and systemic symptoms, usually culminating in death, whereas none of mice receiving dietary green tea extracts exhibited any clinical symptoms or died. Additionally, the combination of green tea extract with levofloxacin increased survival rates and reduced damage to target organs in orally EHEC infected gnotobiotic mice (Isogai et al., 2001). Taken together, these data provide evidence that EGCG has beneficial effects against Shiga toxin-producing E. coli. However, more studies are needed to determine the anti-EHEC effects of EGCG in animal models or clinical trials.

As previously reported for S. maltophilia, EGCG acts as a bisubstrate inhibitor of the bacterial DHFR in E. coli (Spina et al., 2008). Furthermore, results obtained using atomic force microscopy demonstrate that sub-MIC EGCG treatment of E. coli 0157 : H7 leads to temporary changes in the cell walls, such as pore-like lesions or their collapse (Cui et al., 2012). By measuring the intracellular oxidation levels in bacteria after EGCG treatment, it was demonstrated that the morphological changes of gram-negative bacterial cell walls induced by EGCG depend on H2O2 release. As previously shown, one EGCG molecule can produce up to two molecules of H2O2 in phosphate buffer at neutral pH (Arakawa et al., 2004). In conclusion, increasing H2O2 levels resulting in higher oxidative stress is also one mechanism by which EGCG induces a bactericidal effect against gram-negative bacteria. EGCG also produces indirect antibacterial effects on microorganisms; sub-inhibitory concentrations of EGCG can block or significantly reduce the transfer of conjugative R plasmid between E. coli isolates in a dose-dependent manner (Zhao et al., 2001a). This could be of interest because the horizontal transfer of resistance genes by conjugation via plasmids is one of the major mechanisms for dissemination of resistance genes between bacteria. However, future studies are warranted to demonstrate these inhibitory effects against the plasmid-mediated gene transfer of resistance factors in in vitro and in vivo models.

EGCG also has selective immunomodulatory effects on pathogens, as was shown for Legionella pneumophila (Matsunaga et al., 2001). L. pneumophila is an obligate human-pathogenic bacterium that invades and replicates in macrophages. EGCG was demonstrated to inhibit growth of L. pneumophila in macrophages at a concentration as low as 0.5 μg mL−1, without any direct antibacterial effect on the pathogen. The replication was reduced due to selective changes in the immune response of macrophages and enhanced production of pro-inflammatory cytokines.

In conclusion, multiple in vitro and in vivo datasets indicate EGCG has significant direct and indirect anti-pathogenic effects against foodborne bacteria and other gram-negative rods, including multi–drug-resistant strains.

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