New Insights into the Mechanism of Action of the Thienopyrimidine Antitubercular Prodrug TP053

被引:13
作者
Chiarelli, Laurent R. [1 ]
Salina, Elena G. [2 ]
Mori, Giorgia [1 ]
Azhikina, Tatyana [3 ]
Riabova, Olga [2 ]
Lepioshkin, Alexander [2 ]
Grigorov, Artem [3 ]
Forbak, Martin [4 ]
Madacki, Jan [4 ]
Orena, Beatrice Silvia [1 ]
Manfredi, Marcello [5 ,6 ]
Gosetti, Fabio [7 ]
Buzzi, Arianna [7 ]
Degiacomi, Giulia [1 ]
Sammartino, Jose Camilla [1 ]
Marengo, Emilio [7 ]
Kordulakova, Jana [4 ]
Riccardi, Giovanna [1 ]
Mikusova, Katarina [4 ]
Makarov, Vadim [2 ]
Pasca, Maria Rosalia [1 ]
机构
[1] Univ Pavia, Dept Biol & Biotechnol Lazzaro Spallanzani, Via Ferrata 9, I-27100 Pavia, Italy
[2] Russian Acad Sci, Bach Inst Biochem, Res Ctr Biotechnol, Leninsky Prospekt 33-2, Moscow 119071, Russia
[3] Russian Acad Sci, Shemyakin & Ovchinnikov Inst Bioorgan Chem, 16-10 Miklukho Maldaya St, Moscow 117997, Russia
[4] Comenius Univ, Fac Nat Sci, Dept Biochem, Ilkovicova 6,Mlynska Dolina CH1, SK-84215 Bratislava, Slovakia
[5] Univ Piemonte Orientale, Ctr Translat Res Autoimmune & Allerg Dis, Dept Translat Med, Corso Trieste 15, I-28100 Novara, Italy
[6] ISALIT, Spin Off Dept Sci & Technol Innovat, Via A Canobio 4-6, I-28100 Novara, Italy
[7] Univ Piemonte Orientale, Dept Sci & Technol Innovat, Viale Teresa Michel 11, I-15121 Alessandria, Italy
关键词
thienopyrimidine; Mycobacterium tuberculosis; nitric oxide; tuberculosis; mechanism of action; MYCOBACTERIUM-TUBERCULOSIS; RV2466C; RESPIRATION; INHIBITION; RESISTANCE; REDUCTASE; GENE; NO;
D O I
10.1021/acsinfecdis.9b00388
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The thienopyrimidine TP053 is an antitubercular prodrug active against both replicating and non replicating Mycobacterium tuberculosis (M. tuberculosis) cells, which requires activation by the mycothiol-dependent nitroreductase Mrx2. The investigation of the mechanism of action of TP053 revealed that Mrx2 releases nitric oxide from this drug both in the enzyme assays with purified Mrx2 and in mycobacterial cultures, which can explain its activity against nonreplicating bacilli, similar to pretomanid activated by the nitroreductase Ddn. In addition, we identified a highly reactive metabolite, 2-(4-mercapto-6-(methylamino)-2-phenylpyrimidin-5-yl)ethan-1-ol, which can contribute to the antimycobacterial effects on replicating cells as well as on nonreplicating cells. In summary, we explain the mechanism of action of TP053 on both replicating and nonreplicating M. tuberculosis and report a novel activity for Mrx2, which in addition to Ddn, represents another example of nitroreductase releasing nitric oxide from its substrate. These findings are particularly relevant in the context of drugs targeting nonreplicating M. tuberculosis, which is shown to be killed by increased levels of nitric oxide.
引用
收藏
页码:313 / 323
页数:21
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