DprE2 is a molecular target of the anti-tubercular nitroimidazole compounds pretomanid and delamanid.
DprE2 is a molecular target of the anti-tubercular nitroimidazole compounds pretomanid and delamanid.
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DOI：
10.1038/s41467-023-39300-z
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发表时间：
2023-06-28
影响因子：
16.6
通讯作者：
Besra GS
中科院分区：
文献类型：
--
作者：
Abrahams KA;Batt SM;Gurcha SS;Veerapen N;Bashiri G;Besra GS
结核分枝杆菌是由单一传染因子引起的全球主要死亡原因之一。Pretomanid和delamanid是新的抗结核药物，已通过药物发现管道取得进展。这些化合物是双环硝基咪唑，作为前药，需要通过分枝杆菌酶活化;然而，活性代谢物的确切作用机制尚不清楚。在这里，我们确定了激活pretomanid和delamanid的分子靶点：十异戊二烯磷酸核糖-2 '-差向异构酶的DprE 2亚基，这是一种合成细胞壁阿拉伯半乳聚糖所需的酶。我们还提供了NAD加合物作为pretomanid活性代谢产物的证据。我们的研究结果突出了DprE 2作为一个潜在的抗分枝杆菌的目标，并为未来探索pretomanid和delamanid的活性代谢产物和临床开发提供了基础。Pretomanid和delamanid是用于治疗结核病的前药，但其确切的作用机制尚不清楚。在这里，作者确定了合成分枝杆菌细胞壁所需的酶作为活化药物的分子靶点。
Mycobacterium tuberculosis is one of the global leading causes of death due to a single infectious agent. Pretomanid and delamanid are new antitubercular agents that have progressed through the drug discovery pipeline. These compounds are bicyclic nitroimidazoles that act as pro-drugs, requiring activation by a mycobacterial enzyme; however, the precise mechanisms of action of the active metabolite(s) are unclear. Here, we identify a molecular target of activated pretomanid and delamanid: the DprE2 subunit of decaprenylphosphoribose-2’-epimerase, an enzyme required for the synthesis of cell wall arabinogalactan. We also provide evidence for an NAD-adduct as the active metabolite of pretomanid. Our results highlight DprE2 as a potential antimycobacterial target and provide a foundation for future exploration into the active metabolites and clinical development of pretomanid and delamanid. Pretomanid and delamanid are pro-drugs used for the treatment of tuberculosis, but their precise mechanisms of action are unclear. Here, the authors identify an enzyme required for the synthesis of the mycobacterial cell wall as a molecular target of the activated drugs.
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作者：
Batt, Sarah M.;Toth, Szilvi;Rodriguez, Beatriz;Abrahams, Katherine A.;Veerapen, Natacha;Chiodarelli, Giacomo;Cox, Liam R.;Moynihan, Patrick J.;Lelievre, Joel;Futterer, Klaus;Besra, Gurdyal S.
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Besra, Gurdyal S.
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