RbpA and sigma(B) association regulates polyphosphate levels to modulate mycobacterial isoniazid-tolerance
RbpA and sigma(B) association regulates polyphosphate levels to modulate mycobacterial isoniazid-tolerance
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RbpA 和 sigma(B) 关联调节多磷酸盐水平以调节分枝杆菌异烟肼耐受性
DOI：
10.1111/mmi.13952
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发表时间：
2018
影响因子：
3.6
通讯作者：
Hu Yangbo
中科院分区：
文献类型：
--
作者：
Wang Zhongwei;Cumming Bridgette M;Mao Chunyou;Zhu Yan;Lu Pei;Steyn Adrie J C;Chen Shiyun;Hu Yangbo
为了促进在药物应激下的存活，一小部分结核分枝杆菌可以耐受杀菌浓度的药物而不发生基因突变。这些耐药分枝杆菌可由环境压力诱导，并导致非特异性感染。然而，耐药分枝杆菌发展的潜在机制仍然不清楚。在此，我们的特点是一个调节途径，这是重要的耐受异烟肼（INH）在耻垢分枝杆菌。我们发现RNA聚合酶结合蛋白RbpA与应激反应因子σB结合，激活编码多磷酸激酶的基因ppk 1的转录。随后，无机多磷酸盐的细胞内水平增加，以促进INH耐受分枝杆菌。有趣的是，σ Bandppk 1表达在分枝杆菌群体中按比例变化，并且与个体分枝杆菌对INH的耐受性呈正相关。此外，sigBandppk 1转录都是在营养耗尽时诱导的，这是一种刺激INH耐受分枝杆菌形成的条件。rbpA敲除或sigB缺失菌株中ppk 1的过表达成功地恢复了正常生长和营养饥饿条件下INH耐受分枝杆菌的数量。这些数据表明，在对数生长期和营养饥饿条件下，RbpA和σ B调节ppk 1表达以控制药物耐受性。
To facilitate survival under drug stresses, a small population ofMycobacterium tuberculosiscan tolerate bactericidal concentrations of drugs without genetic mutations. These drug‐tolerant mycobacteria can be induced by environmental stresses and contribute to recalcitrant infections. However, mechanisms underlying the development of drug‐tolerant mycobacteria remain obscure. Herein, we characterized a regulatory pathway which is important for the tolerance to isoniazid (INH) inMycobacterium smegmatis. We found that the RNA polymerase binding protein RbpA associates with the stress response sigma factor σB, to activate the transcription ofppk1, the gene encoding polyphosphate kinase. Subsequently, intracellular levels of inorganic polyphosphate increase to promote INH‐tolerant mycobacteria. Interestingly, σBandppk1expression varied proportionately in mycobacterial populations and positively correlated with tolerance to INH in individual mycobacteria. Moreover,sigBandppk1transcription are both induced upon nutrient depletion, a condition that stimulates the formation of INH‐tolerant mycobacteria. Over‐expression ofppk1inrbpAknockdown orsigBdeleted strains successfully restored the number of INH‐tolerant mycobacteria under both normal growth and nutrient starved conditions. These data suggest that RbpA and σBregulateppk1expression to control drug tolerance both during the logarithmic growth phase and under the nutrition starved conditions.