Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents
Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents
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DOI：
10.1073/pnas.0909133107
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发表时间：
2010-03-09
影响因子：
11.1
通讯作者：
Zhang, Zhong-Yin
中科院分区：
文献类型：
--
作者：
Zhou, Bo;He, Yantao;Zhang, Zhong-Yin
蛋白酪氨酸磷酸酶常被致病菌利用和破坏而引起人类疾病。来自结核分枝杆菌的酪氨酸磷酸酶mPTPB是由细菌分泌到巨噬细胞的细胞质中的必需毒力因子，在巨噬细胞的细胞质中其介导分枝杆菌在宿主中的存活。因此，有相当大的兴趣，了解mPTPB逃避宿主免疫反应的机制，并在开发有效的和选择性的mPTPB抑制剂作为独特的抗结核病（抗TB）剂。我们发现mPTPB通过阻断ERK 1/2和p38介导的IL-6产生来破坏先天免疫应答，并通过激活Akt通路来促进宿主细胞存活。我们从通过点击化学组装的双齿苯并呋喃水杨酸衍生物的组合文库中鉴定出具有高效细胞活性的有效和选择性mPTPB抑制剂I-A09。我们证明了在巨噬细胞中用I-A09抑制mPTPB逆转了由细菌磷酸酶诱导的改变的宿主免疫应答，并防止宿主细胞中的TB生长。这些结果提供了必要的原理验证数据，以支持mPTPB的特异性抑制剂可作为有效的抗TB治疗剂的概念。
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.