Discovery of uncompetitive inhibitors of SapM that compromise intracellular survival of Mycobacterium tuberculosis.
Discovery of uncompetitive inhibitors of SapM that compromise intracellular survival of Mycobacterium tuberculosis.
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DOI：
10.1038/s41598-021-87117-x
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发表时间：
2021-04-07
影响因子：
4.6
通讯作者：
Tabernero L
中科院分区：
文献类型：
--
作者：
Fernández-Soto P;Casulli J;Solano-Castro D;Rodríguez-Fernández P;Jowitt TA;Travis MA;Cavet JS;Tabernero L
SapM是结核分枝杆菌分泌的毒力因子，对病原体在宿主体内的存活和持久性至关重要。由于缺乏有效的抑制剂，其作为结核病治疗靶点的全部潜力尚未得到开发。通过筛选超过1500个小分子，我们已经确定了新的有效的和选择性的抑制剂SapM的非竞争性抑制机制。最好的抑制剂都有一个对活性至关重要的三羟基苯部分。重要的是，抑制剂在1 µM时可显著降低感染的人巨噬细胞中的分枝杆菌负荷，并且它们对其他分枝杆菌和人磷酸酶具有选择性。最好的抑制剂还减少土拉弗朗西斯菌的细胞内负荷，土拉弗朗西斯菌分泌毒力因子AcpA，SapM的同源物，具有相同的催化和抑制机制。我们的研究结果表明，用小分子抑制剂抑制SapM可以有效减少宿主巨噬细胞中细胞内分枝杆菌的存活，并证实SapM是潜在的治疗靶点。这些初始化合物具有有利的物理化学性质，并为探索开发新的结核病治疗方法提供了基础。SapM抑制剂在降低土拉热弗朗西丝菌细胞内负荷方面的功效表明了开发广谱抗病毒剂以治疗微生物感染的潜力。
SapM is a secreted virulence factor from Mycobacterium tuberculosis critical for pathogen survival and persistence inside the host. Its full potential as a target for tuberculosis treatment has not yet been exploited because of the lack of potent inhibitors available. By screening over 1500 small molecules, we have identified new potent and selective inhibitors of SapM with an uncompetitive mechanism of inhibition. The best inhibitors share a trihydroxy-benzene moiety essential for activity. Importantly, the inhibitors significantly reduce mycobacterial burden in infected human macrophages at 1 µM, and they are selective with respect to other mycobacterial and human phosphatases. The best inhibitor also reduces intracellular burden of Francisella tularensis, which secretes the virulence factor AcpA, a homologue of SapM, with the same mechanism of catalysis and inhibition. Our findings demonstrate that inhibition of SapM with small molecule inhibitors is efficient in reducing intracellular mycobacterial survival in host macrophages and confirm SapM as a potential therapeutic target. These initial compounds have favourable physico-chemical properties and provide a basis for exploration towards the development of new tuberculosis treatments. The efficacy of a SapM inhibitor in reducing Francisella tularensis intracellular burden suggests the potential for developing broad-spectrum antivirulence agents to treat microbial infections.
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影响因子：
11.2
作者：
Kim, Dong Joon;Li, Yan;Dong, Zigang
通讯作者：
Dong, Zigang
影响因子：
3.2
作者：
Koul, A;Choidas, A;Ullrich, A
通讯作者：
Ullrich, A
影响因子：
3.4
作者：
Manerba, Marcella;Vettraino, Marina;Recanatini, Maurizio
通讯作者：
Recanatini, Maurizio
影响因子：
3.2
作者：
Fujiwara, Mamoru;Kawasaki, Masanori;Matsumoto, Makoto
通讯作者：
Matsumoto, Makoto
DOI：
10.1158/1078-0432.ccr-09-2434
发表时间：
2010-01-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Evers B;Schut E;van der Burg E;Braumuller TM;Egan DA;Holstege H;Edser P;Adams DJ;Wade-Martins R;Bouwman P;Jonkers J
通讯作者：
Jonkers J