Noise in a Metabolic Pathway Leads to Persister Formation in Mycobacterium tuberculosis.
Noise in a Metabolic Pathway Leads to Persister Formation in Mycobacterium tuberculosis.
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DOI：
10.1128/spectrum.02948-22
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发表时间：
2022-10-26
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
由于响应免疫应激而形成的休眠细胞和随机形成的持续细胞，结核病很难治疗，这两种细胞都对抗生素具有耐受性。杀菌抗生素通过破坏其依赖能量的靶标来杀死细菌。我们推断，能量产生成分表达中的随机变化或噪音将产生稀有的持久细胞。在醋酸盐上生长的分选结核分枝杆菌细胞中，编码醋酸激酶 AckA 的 mRNA 水平存在相当大的细胞间差异。通过过度表达 ackA 来消除噪音会急剧减少持久基因，表明它在这些条件下充当主要的持久基因。这表明低能量机制是结核分枝杆菌持续存在的形成的原因。由产生能量的酶表达中的噪音驱动进入低能量状态可能是细菌产生持久性的一般机制。重要性 结核分枝杆菌感染需要长期使用多种抗生素。治疗困难通常归因于结核分枝杆菌进入非复制、抗生素耐受状态。结核分枝杆菌响应免疫应激而进入这种非复制状态。然而，在没有任何应激的正常生长条件下，一小群细胞会进入非复制、多药耐受状态。这些细胞被称为持久细胞。持久化者进入非复制状态的机制很大程度上是未知的。在这里，我们表明，与其他细菌一样，结核分枝杆菌持续存在是在正常生长过程中随机形成的低能量细胞。此外，我们确定能量产生基因表达的自然变异是结核分枝杆菌随机进入低能量持续状态的来源。这些发现对于了解结核分枝杆菌感染的异质性具有重要意义，并将有助于针对这种重要的人类病原体设计更好的治疗方案。
Tuberculosis is difficult to treat due to dormant cells formed in response to immune stress and stochastically formed persisters, both of which are tolerant of antibiotics. Bactericidal antibiotics kill by corrupting their energy-dependent targets. We reasoned that stochastic variation, or noise, in the expression of an energy-generating component will produce rare persister cells. In sorted M. tuberculosis cells grown on acetate, there is considerable cell-to-cell variation in the level of mRNA coding for AckA, the acetate kinase. Quenching the noise by overexpressing ackA sharply decreases persisters, showing that it acts as the main persister gene under these conditions. This demonstrates that a low energy mechanism is responsible for the formation of M. tuberculosis persisters. Entrance into a low-energy state driven by noise in expression of energy-producing enzymes is likely a general mechanism by which bacteria produce persisters. IMPORTANCE M. tuberculosis infection requires the administration of multiple antibiotics for a prolonged period of time. Treatment difficulty is generally attributed to M. tuberculosis entrance into a nonreplicative, antibiotic-tolerant state. M. tuberculosis enters this nonreplicative state in response to immune stress. However, a small population of cells enter a nonreplicative, multidrug-tolerant state under normal growth conditions, absent any stress. These cells are termed persisters. The mechanisms by which persisters enter a nonreplicative state are largely unknown. Here, we show that, as with other bacteria, M. tuberculosis persisters are low-energy cells formed stochastically during normal growth. Additionally, we identify the natural variation in the expression of energy producing genes as a source of the stochastic entrance of M. tuberculosis into the low-energy persister state. These findings have important implications for understanding the heterogeneous nature of M. tuberculosis infection and will aid in designing better treatment regimens against this important human pathogen.
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影响因子：
16.6
作者：
Koul, Anil;Vranckx, Luc;Dhar, Neeraj;Gohlmann, Hinrich W. H.;Oezdemir, Emre;Neefs, Jean-Marc;Schulz, Melanie;Lu, Ping;Mortz, Ejvind;McKinney, John D.;Andries, Koen;Bald, Dirk
通讯作者：
Bald, Dirk
影响因子：
6.4
作者：
Keren I;Minami S;Rubin E;Lewis K
通讯作者：
Lewis K
DOI：
10.1073/pnas.83.16.6164
发表时间：
1986-08-01
影响因子：
11.1
作者：
DAVIS, BD;CHEN, LL;TAI, PC
通讯作者：
TAI, PC
影响因子：
16
作者：
Amato, Stephanie M.;Orman, Mehmet A.;Brynildsen, Mark P.
通讯作者：
Brynildsen, Mark P.
影响因子：
3.6
作者：
Berghoff, Bork A.;Hoekzema, Mirthe;Wagner, E. Gerhart H.
通讯作者：
Wagner, E. Gerhart H.