Aspartate decarboxylase (PanD) as a new target of pyrazinamide in Mycobacterium tuberculosis.
Aspartate decarboxylase (PanD) as a new target of pyrazinamide in Mycobacterium tuberculosis.
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天冬氨酸脱羧酶（PanD）作为结核分枝杆菌中吡嗪酰胺的新靶点
DOI：
10.1038/emi.2014.61
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发表时间：
2014-08
影响因子：
13.2
通讯作者：
Zhang, Ying
中科院分区：
文献类型：
--
作者：
Shi, Wanliang;Chen, Jiazhen;Feng, Jie;Cui, Peng;Zhang, Shuo;Weng, Xinhua;Zhang, Wenhong;Zhang, Ying
吡嗪酰胺（PZA）是一种一线抗结核药物，在治疗药物敏感和耐多药结核病（MDR-TB）方面发挥着至关重要的作用。PZA是一种前药，通过pncA基因编码的烟酰胺酶/吡嗪酰胺酶转化为其活性形式吡嗪酸（POA），pncA基因的突变是PZA耐药性的主要原因。虽然RpsA（核糖体蛋白S1，参与反式翻译）最近已被证明是一个目标的POA/PZA，全基因组测序已确定突变的panD基因编码天冬氨酸脱羧酶的PZA耐药菌株缺乏pncA和rpsA突变。为了更深入地了解PZA可能的新靶点，我们从M.结核病的体外研究，以及3个突变体的全基因组测序鉴定了panD基因中的各种突变。此外，测序分析显示，剩余的27个POA抗性突变体都具有影响PanD蛋白C-末端的PanD突变，其中PanD M117 I是最常见的突变（24/30，80%）。从M.结核分枝杆菌（M. smegalgae或E. coli或M.结核分枝杆菌PanDM 117 I突变株对POA和PZA均产生耐药性。结核PanD的下游产物β-丙氨酸和泛酸可拮抗POA的抗结核活性。此外，还研究了M.结核PanD酶被治疗相关浓度的POA以浓度依赖性方式抑制，但不被前药PZA或对照化合物烟酰胺抑制。这些发现表明PanD代表PZA/POA的新靶点。这些结果对于更好地理解这种特殊的持久性药物和设计靶向M的新药具有重要意义。肺结核持续存在，以改善治疗。
Pyrazinamide (PZA) is a frontline anti-tuberculosis drug that plays a crucial role in the treatment of both drug-susceptible and multidrug-resistant tuberculosis (MDR-TB). PZA is a prodrug that is converted to its active form, pyrazinoic acid (POA), by a nicotinamidase/pyrazinamidase encoded by the pncA gene, the mutation of which is the major cause of PZA resistance. Although RpsA (ribosomal protein S1, involved in trans-translation) has recently been shown to be a target of POA/PZA, whole-genome sequencing has identified mutations in the panD gene encoding aspartate decarboxylase in PZA-resistant strains lacking pncA and rpsA mutations. To gain more insight into a possible new target of PZA, we isolated 30 POA-resistant mutants lacking mutations in pncA and rpsA from M. tuberculosis in vitro, and whole-genome sequencing of 3 mutants identified various mutations in the panD gene. Additionally, sequencing analysis revealed that the remaining 27 POA-resistant mutants all harbored panD mutations affecting the C-terminus of the PanD protein, with PanD M117I being the most frequent mutation (24/30, 80%). Conditional overexpression of panD from M. tuberculosis, M. smegmatis or E. coli, or of M. tuberculosis mutant PanD M117I, all conferred resistance to POA and PZA in M. tuberculosis. β-alanine and pantothenate, which are downstream products of PanD, were found to antagonize the antituberculosis activity of POA. In addition, the activity of the M. tuberculosis PanD enzyme was inhibited by POA at therapeutically relevant concentrations in a concentration-dependent manner but was not inhibited by the prodrug PZA or the control compound nicotinamide. These findings suggest that PanD represents a new target of PZA/POA. These results have implications for a better understanding of this peculiar persister drug and for the design of new drugs targeting M. tuberculosis persisters for improved treatment.
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影响因子：
3.7
作者：
Sharma R;Kothapalli R;Van Dongen AM;Swaminathan K
通讯作者：
Swaminathan K
DOI：
10.1126/science.1208813
发表时间：
2011-09-16
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Shi W;Zhang X;Jiang X;Yuan H;Lee JS;Barry CE 3rd;Wang H;Zhang W;Zhang Y
通讯作者：
Zhang Y
影响因子：
2.9
作者：
Gopalan, Gayathri;Chopra, Sidharth;Swaminathan, Kunchithapadam
通讯作者：
Swaminathan, Kunchithapadam
影响因子：
13.2
作者：
Zhang, Ying;Chang, Kwok Chiu;Leung, Chi-Chiu;Yew, Wing Wai;Gicquel, Brigitte;Fallows, Dorothy;Kaplan, Gilla;Chaisson, Richard E.;Zhang, Wenhong
通讯作者：
Zhang, Wenhong
影响因子：
3.7
作者：
Darby CM;Ingólfsson HI;Jiang X;Shen C;Sun M;Zhao N;Burns K;Liu G;Ehrt S;Warren JD;Andersen OS;Brickner SJ;Nathan C
通讯作者：
Nathan C