Protein tyrosine phosphatases are often exploited and subverted by pathogenic bacteria to cause human diseases. The tyrosine phosphatase mPTPB from Mycobacterium tuberculosis is an essential virulence factor that is secreted by the bacterium into the cytoplasm of macrophages, where it mediates mycobacterial survival in the host. Consequently, there is considerable interest in understanding the mechanism by which mPTPB evades the host immune responses, and in developing potent and selective mPTPB inhibitors as unique antituberculosis (antiTB) agents. We uncovered that mPTPB subverts the innate immune responses by blocking the ERK1/2 and p38 mediated IL-6 production and promoting host cell survival by activating the Akt pathway. We identified a potent and selective mPTPB inhibitor I-A09 with highly efficacious cellular activity, from a combinatorial library of bidentate benzofuran salicylic acid derivatives assembled by click chemistry. We demonstrated that inhibition of mPTPB with I-A09 in macrophages reverses the altered host immune responses induced by the bacterial phosphatase and prevents TB growth in host cells. The results provide the necessary proof-of-principle data to support the notion that specific inhibitors of the mPTPB may serve as effective antiTB therapeutics.combinatorial chemistry | pathogen-host interaction | phosphatase inhibitor | signaling mechanism

Scope Polyphenol‐enriched herbal extracts have been proved as alternative therapeutic strategies for experimentally induced colitis. The in vivo and in vitro anti‐inflammatory effects of Camellia sinensis (green, white, yellow, oolong, black, and dark tea) and Litsea coreana (hawk tea) are comparatively explored. Methods and results HPLC analysis confirms dissimilarities among phytochemical compositions of these teas. The tea extracts (TEs) significantly decrease the production of pro‐inflammatory cytokines (IL‐6, IL‐12, and tumor necrosis factor‐α) and increase the anti‐inflammatory cytokines (IL‐10) in LPS‐stimulated RAW 264.7 macrophages and a dextran sodium sulfate (DSS)‐induced colitis mouse model. The treatment of TEs in colitis mice can ameliorate colon inflammation, pro‐oxidative enzyme activity, colon integrity, and suppress the activation of nuclear factor‐κB. Of note, green TE significantly attenuates the DSS‐induced decrease in richness and diversity of gut microbiota. Moreover, TEs are capable of exerting a prebiotic effect on gut microbiota by increasing the abundance of potentially beneficial bacteria (e.g., Faecalibaculum, and Bifidobacterium), and decreasing the abundance of potentially harmful bacteria (e.g., Bacteroids, and Mucispirillum). TEs restore the decreased production of SCFAs in the feces of colitic mice. Conclusion The treatment of seven types of tea can alleviate DSS‐induced colitis in mice, and modulate the dysbiosis of gut microbiota in colitis mice.

Green and dark tea extract (GTE/DTE) ameliorate chemical-induced colitis in mice; however, the role of gut microbiota in the anticolitis effects of green and dark tea in mice remains unclear. This study aims to explore the role of modulations in gut microbes mediated by green and dark tea in colitis mice by fecal microbiota transplantation (FMT). Our results indicated that GTE and DTE (5 mg/kg bodyweight/day for 4 weeks) exhibited prebiotic effects on the donor mice. Moreover, the FMT treatments (transferring the microbiota daily from the 1 g/kg bodyweight fecal sample to each recipient) indicated that, compared with the fecal microbiota from the normal diet-treated donor mice, the fecal microbiota from the GTE- and DTE-treated donor mice significantly ameliorate colitis-related symptoms (e.g., loss of bodyweight, colonic inflammation, loss of barrier integrity, and gut microbiota dysbiosis) and downregulated the TLR4/MyD88/NF-κB pathway. Collectively, GTE and DTE ameliorate chemical-induced colitis by modulating gut microbiota.

Ripened pu-erh tea has the biological activity of antioxidation and anti-inflammation, which inhibits the related parameters of colitis. However, the role of storage-induced changes in bioactive ingredients of ripened pu-erh tea in colitis remains unclear. In this study, 3.5% dextran sulfate sodium-induced colitis mice were treated with 10 mg/kg bw/day extracts, aged 14 years (P2006) and unaged (P2020) ripened pu-erh tea, respectively, for 1 week. We found that ripened pu-erh tea, especially P2006, inhibited the intestinal oxidative stress-mediated inflammation pathway (TLR4/MyD88/ROS/p38MAPK/NF-κB p65), upregulated the expression of intestinal tight junction proteins (Mucin-2, ZO-1, occludin), promoted M2 polarization of macrophages, and in turn, improved the intestinal immune barrier, which stemmed from the reshaping of intestinal microbiota (e.g., increased Lachnospiraceae_NK4A136_group and Akkermansia levels). Our results speculate that drinking aged ripe pu-erh tea (10 mg/kg bw/ day in mice, a human equivalent dose of 7 g/60 kg bw/day) has a practical effect on alleviating and preventing the development of intestinal inflammation.

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