Global transcriptional profiling of longitudinal clinical isolates of Mycobacterium tuberculosis exhibiting rapid accumulation of drug resistance.
Global transcriptional profiling of longitudinal clinical isolates of Mycobacterium tuberculosis exhibiting rapid accumulation of drug resistance.
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DOI：
10.1371/journal.pone.0054717
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Mistry N
中科院分区：
文献类型：
--
作者：
Chatterjee A;Saranath D;Bhatter P;Mistry N
在孟买等脆弱地区，多重耐药（MDR）、广泛和完全耐药结核分枝杆菌（Mtb）的发现对结核病控制构成严重威胁。目前的研究旨在解释 MDR 在符合直接观察治疗短期疗程 (DOTS) 的患者中的快速表达，这是第一项比较 3 对临床 Mtb 分离株整体转录谱的研究，这些菌株是在 DOTS 开始和完成时纵向收集的。虽然这些分离株在发病时是药物敏感 (DS)，在 DOTS 完成时是 MDR，但它们在两个收集点都表现出相同的 DNA 指纹。使用来自 H37Rv 和 3 种局部优势 spoligotypes 的总 RNA 进行全基因组转录分析。 MANU1、CAS和Beijing在MTBv3(BuG@S)微阵列上杂交，分别产生36、98和45个差异表达基因。与相同基因型的 DS 分离株相比，编码转录因子（sig、rpoB）、细胞壁生物合成（emb 基因）、蛋白质合成（rpl）和其他中央代谢途径（ppdK、pknH、pfkB）的基因在 MDR 分离株中下调。在 MDR 分离株中观察到药物外排泵、ABC 转运蛋白、跨膜蛋白和应激反应转录因子 (whiB) 的上调。数据表明，由于药物外排泵和代谢率降低等额外机制，药物靶基因没有特定突变的结核分枝杆菌可能会在宿主体内持续存在。此外，该 Mtb 群体也表现出 DNA 修复活性降低，将导致药物靶基因自发突变的选择和稳定，从而在药物压力存在的情况下导致 MDR 菌株的选择。 drrA 等外排泵可能在提高低水平耐药细胞的适应性方面发挥重要作用，并有助于 Mtb 的生存，直到以最低的适应性成本获得耐药突变。
The identification of multidrug resistant (MDR), extensively and totally drug resistant Mycobacterium tuberculosis (Mtb), in vulnerable sites such as Mumbai, is a grave threat to the control of tuberculosis. The current study aimed at explaining the rapid expression of MDR in Directly Observed Treatment Short Course (DOTS) compliant patients, represents the first study comparing global transcriptional profiles of 3 pairs of clinical Mtb isolates, collected longitudinally at initiation and completion of DOTS. While the isolates were drug susceptible (DS) at onset and MDR at completion of DOTS, they exhibited identical DNA fingerprints at both points of collection. The whole genome transcriptional analysis was performed using total RNA from H37Rv and 3 locally predominant spoligotypes viz. MANU1, CAS and Beijing, hybridized on MTBv3 (BuG@S) microarray, and yielded 36, 98 and 45 differentially expressed genes respectively. Genes encoding transcription factors (sig, rpoB), cell wall biosynthesis (emb genes), protein synthesis (rpl) and additional central metabolic pathways (ppdK, pknH, pfkB) were found to be down regulated in the MDR isolates as compared to the DS isolate of the same genotype. Up regulation of drug efflux pumps, ABC transporters, trans-membrane proteins and stress response transcriptional factors (whiB) in the MDR isolates was observed. The data indicated that Mtb, without specific mutations in drug target genes may persist in the host due to additional mechanisms like drug efflux pumps and lowered rate of metabolism. Furthermore this population of Mtb, which also showed reduced DNA repair activity, would result in selection and stabilization of spontaneous mutations in drug target genes, causing selection of a MDR strain in the presence of drug pressures. Efflux pump such as drrA may play a significant role in increasing fitness of low level drug resistant cells and assist in survival of Mtb till acquisition of drug resistant mutations with least fitness cost.
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DOI：
10.1073/pnas.1003219107
发表时间：
2010-07-06
影响因子：
11.1
作者：
Dhar, Neeraj;McKinney, John D.
通讯作者：
McKinney, John D.
影响因子：
2.6
作者：
Jiang, Xin;Zhang, Wenhong;Wang, Honghai
通讯作者：
Wang, Honghai
影响因子：
3.2
作者：
De Rossi, E;Branzoni, M;Ciferri, O
通讯作者：
Ciferri, O
影响因子：
9.4
作者：
Kamerbeek, J;Schouls, L;vanEmbden, J
通讯作者：
vanEmbden, J
影响因子：
3.1
作者：
Fontan, Patricia;Aris, Virginie;Smith, Issar
通讯作者：
Smith, Issar