Selective killing of nonreplicating mycobacteria
Selective killing of nonreplicating mycobacteria
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DOI：
10.1016/j.chom.2008.02.003
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发表时间：
2008-03-01
影响因子：
30.3
通讯作者：
Nathan, Carl
中科院分区：
文献类型：
--
作者：
Bryk, Ruslana;Gold, Benjamin;Nathan, Carl
抗生素通常对复制细菌比非复制细菌更有效。然而，全球健康的一个主要需求是根除持久性或非复制性细菌亚群，例如结核分枝杆菌 (Mtb)。因此，识别选择性杀死不复制细菌的化学抑制剂具有实际意义。为了解决这个问题，我们筛选了二氢硫辛酰胺酰基转移酶 (DlaT) 的抑制剂，这是结核分枝杆菌所需的一种酶，可在豚鼠中引起结核病，并被细菌用来抵抗一氧化氮衍生的活性氮中间体，这是宿主遇到的一种应激。 Mtb DlaT 抑制剂的化学筛选确定了精选的绕丹宁化合物，它们与宿主免疫产物（例如一氧化氮和缺氧）协同作用，几乎完全杀死非复制分枝杆菌，并且对巨噬细胞（潜伏 Mtb 的细胞储存库）内的细菌有效。与宿主免疫配合杀死非复制病原体的化合物可以补充传染病的常规化疗。
Antibiotics are typically more effective against replicating rather than nonreplicating bacteria. However, a major need in global health is to eradicate persistent or nonreplicating subpopulations of bacteria such as Mycobacterium tuberculosis (Mtb). Hence, identifying chemical inhibitors that selectively kill bacteria that are not replicating is of practical importance. To address this, we screened for inhibitors of dihydrolipoamide acyltransferase (DlaT), an enzyme required by Mtb to cause tuberculosis in guinea pigs and used by the bacterium to resist nitric oxide-derived reactive nitrogen intermediates, a stress encountered in the host. Chemical screening for inhibitors of Mtb DlaT identified select rhodanines as compounds that almost exclusively kill nonreplicating mycobacteria in synergy with products of host immunity, such as nitric oxide and hypoxia, and are effective on bacteria within macrophages, a cellular reservoir for latent Mtb. Compounds that kill nonreplicating pathogens in cooperation with host immunity could complement the conventional chemotherapy of infectious disease.