Discovery of a capuramycin analog that kills nonreplicating Mycobacterium tuberculosis and its synergistic effects with translocase I inhibitors

Siricilla Shajila; Mitachi Katsuhiko; Wan Bajoie; Franzblau Scott G.; Kurosu Michio

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Discovery of a capuramycin analog that kills nonreplicating Mycobacterium tuberculosis and its synergistic effects with translocase I inhibitors

机译：发现一种可杀死非复制型结核分枝杆菌的卡普拉霉素类似物及其与转位酶I抑制剂的协同作用

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Capuramycin (1) and its analogs are strong translocase I (MurX/MraY) inhibitors. In our structure-activity relationship studies of capuramycin analogs against Mycobacterium tuberculosis (Mtb), we observed for the first time that a capuramycin analog, UT-01320 (3) killed nonreplicating (dormant) Mtb at low concentrations under low oxygen conditions, whereas selective MurX inhibitors killed only replicating Mtb under aerobic conditions. Interestingly, 3 did not exhibit MurX enzyme inhibitory activity even at high concentrations, however, 3 inhibited bacterial RNA polymerases with the IC50 values of 100-150 nM range. A new RNA polymerase inhibitor 3 displayed strong synergistic effects with a MurX inhibitor SQ 641 (2), a promising preclinical tuberculosis drug.

机译：Capuramycin（1）及其类似物是强转位酶I（MurX / MraY）抑制剂。在我们的卡普拉霉素类似物抗结核分枝杆菌（Mtb）的结构-活性关系研究中，我们首次观察到卡普拉霉素类似物UT-01320（3）在低氧条件下以低浓度杀死了非复制型（休眠）Mtb，而选择性MurX抑制剂在有氧条件下仅杀死复制的Mtb。有趣的是，即使在高浓度下，也有3个没有表现出MurX酶抑制活性，但是，有3个抑制了细菌RNA聚合酶，IC50值为100-150 nM。一种新型的RNA聚合酶抑制剂3与有希望的临床前结核病药物MurX抑制剂SQ 641（2）表现出强大的协同作用。

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《The Journal of Antibiotics: An International Journal》 |2015年第4期|共8页
作者
Siricilla Shajila; Mitachi Katsuhiko; Wan Bajoie; Franzblau Scott G.; Kurosu Michio;
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正文语种 eng
中图分类药学;
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1. Discovery of a capuramycin analog that kills nonreplicating Mycobacterium tuberculosis and its synergistic effects with translocase I inhibitors [J] . Siricilla Shajila, Mitachi Katsuhiko, Wan Bajoie, The Journal of Antibiotics: An International Journal . 2015,第4期

机译：发现一种可杀死非复制型结核分枝杆菌的卡普拉霉素类似物及其与转位酶I抑制剂的协同作用
2. Aminopyrazinamides: Novel and specific GyrB inhibitors that kill replicating and nonreplicating mycobacterium tuberculosis [J] . Shirude P.S., Madhavapeddi P., Tucker J.A., ACS Chemical Biology . 2013,第3期

机译：氨基吡嗪酰胺：新型和特异性的GyrB抑制剂，可杀死复制型和非复制型结核分枝杆菌
3. Discovery of novel 5-(ethyl or hydroxymethyl) analogs of 2′-'up' fluoro (or hydroxyl) pyrimidine nucleosides as a new class of Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium avium inhibitors [J] . ShakyaN., SrivastavN.C., BhavanamS., Bioorganic and medicinal chemistry . 2012,第13期

机译：发现2'-'up'氟（或羟基）嘧啶核苷的新型5-（乙基或羟甲基）类似物，作为结核分枝杆菌，牛分枝杆菌和鸟分枝杆菌抑制剂的新类别
4. MONITORING RESPONSES BY USE OF 5-COLOR FLOW CYTOMETRY IN SUBSETS OF PERIPHERAL T CELLS OBTAINED FROM CATTLE INOCULATED WITH A KILLED MYCOBACTERIUM AVIUM SUBSPECIES PARATUBERCULOSIS VACCINE [C] . Ratree Platt, James A. Roth, Charles O. Thoen, Annual Meeting of the United States Animal Health Association . 2007

机译：通过使用5色流式细胞术在从牛接种的牛渣中获得的外周T细胞亚包中的亚包进行监测反应患有杀死的分枝杆菌亚种分枝疫苗疫苗
5. Identification of a Phosphopantetheinyl Transferase Inhibitor That Kills Mycobacterium tuberculosis and a Novel Mechanism of Resistance Involving an Enzyme of Previously Unknown Function: Phosphopantetheinyl Hydrolase [D] . Ballinger, Elaine. 2018

机译：鉴定杀灭结核分枝杆菌的磷酸乙酰基转移酶抑制剂和一种涉及先前未知功能酶的新型抗性机制：磷酸乙基乙基水解酶
6. Discovery of a capuramycin analog that kills non-replicating Mycobacterium tuberculosis and its synergistic effects with translocase I inhibitors [O] . Shajila Siricilla, Katsuhiko Mitachi, Bajoie Wan, -1

机译：发现一种可杀死非复制型结核分枝杆菌的卡普拉霉素类似物及其与转位酶I抑制剂的协同作用
7. Dual-Pharmacophore Pyrithione-Containing Cephalosporins Kill Both Replicating and Nonreplicating Mycobacterium tuberculosis [O] . -1

机译：含有双药光氨基硫酮的头孢菌素杀死复制和不加速的分枝杆菌

Discovery of a capuramycin analog that kills nonreplicating Mycobacterium tuberculosis and its synergistic effects with translocase I inhibitors

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