结核分枝杆菌毒力因子蛋白酪氨酸磷酸酶PtpA转录调控和分泌机理

结核分枝杆菌感染引起的结核病疫情依然严峻。感染的结核菌可分泌一系列效应分子调控、干扰和逃逸宿主免疫。本文综述蛋白酪氨酸磷酸酶PtpA在结核菌感染中发挥的重要作用:经多条途径抑制宿主天然免疫、细胞凋亡及吞噬体-溶酶体融合、调控宿主能量代谢等逃逸免疫杀伤。作为候选药物靶标,靶向PtpA的抑制剂设计、筛选及药物研发较为迟缓,因为PtpA与宿主蛋白酪氨酸磷酸酶hLMW-PTP具有较高一致性。为了进一步探索靶向该分子的更佳途径,分析了ptpA基因转录及PtpA蛋白分泌方面的研究进展及存在问题,为靶向PtpA的其他途径提供参考。     

Protein kinase and phosphatase signaling in Mycobacterium tuberculosis physiology and pathogenesis

Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB), evades the antimicrobial defenses of the host and survives within the infected individual through a complex set of strategies. These include active prevention of host cellular killing processes as well as overwhelming adaptive gene expression. In the past decade, we have gained an increased understanding of how mycobacteria not only have the ability to adapt to a changing host environment but also actively interfere with the signaling machinery within the host cell to counteract or inhibit parts of the killing apparatus employed by the macrophage. Mtb is able to sense its environment via a set of phospho-signaling proteins which mediate its response and interaction with the host in a coordinated manner. In this review, we summarize the current knowledge about selected Mtb serine, threonine, and tyrosine kinase and phosphatase signaling proteins, focusing on the protein kinases, PknG and PtkA, and the protein phosphatase, PtpA.     

Synthetic thiosemicarbazones as a new class of Mycobacterium tuberculosis protein tyrosine phosphatase A inhibitors

Mycobacterium tuberculosis secretes two protein tyrosine phosphatases as virulence factors, PtpA and PtpB. Inhibition studies of these enzymes have shown significant attenuation of the M. tuberculosis growth in vivo. As PtpA mediates many effects on the regulation of host signaling ensuring the intracellular survival of the bacterium we report, for the first time, thiosemicarbazones as potential novel class of PtpA inhibitors. Several compounds were synthesized and biologically evaluated, revealing interesting results. Enzyme kinetic assays showed that compounds 5, 9 and 18 are non-competitive inhibitors of PtpA, with K_i values ranging from 1.2 to 5.6?µM. Modeling studies clarified the structure-activity relationships observed in vitro and indicated a possible allosteric binding site in PtpA structure. To the best of our knowledge, this is the first disclosure of potent non-competitive inhibitors of PtpA with great potential for future studies and development of analogues.