Evolution of extensively drug-resistant Mycobacterium tuberculosis from a susceptible ancestor in a single patient.
Evolution of extensively drug-resistant Mycobacterium tuberculosis from a susceptible ancestor in a single patient.
复制标题
DOI：
10.1186/s13059-014-0490-3
复制
发表时间：
2014-11-07
期刊：
影响因子：
12.3
通讯作者：
Balloux F
中科院分区：
文献类型：
--
作者：
Eldholm V;Norheim G;von der Lippe B;Kinander W;Dahle UR;Caugant DA;Mannsåker T;Mengshoel AT;Dyrhol-Riise AM;Balloux F
结核分枝杆菌的特点是突变率低和缺乏基因重组。然而，广泛耐药菌株的出现描绘了一幅具有令人印象深刻的适应潜力的微生物的画面。在这里，我们描述了第一例记录在案的广泛耐药结核病从一个易感的祖先在一个单一的病人。9个系列M.来自同一患者的结核病分离物揭示了由单核苷酸多态性的出现和随后的固定或丢失驱动的竞争谱系的急剧更替。对于大多数药物来说，耐药性是通过在一个以上的克隆中独立出现突变而产生的，其中只有一个克隆最终占上风，因为携带它的克隆扩大了，在这个过程中取代了其他克隆。在3.5年内发现的绝大多数突变要么与耐药性有关，要么与这些基因背景有关。此外，在没有药物激发的情况下生长的分离株的RNA测序显示，流出相关的iniBAC操纵子随时间上调，而下调的基因包括参与分枝菌酸合成的基因。我们观察到由单个突变介导的对抗菌化合物的耐药性的快速获得，以及在抗生素存在下适应性的逐渐增加，这可能是由稳定的基因表达重编程驱动的。耐药突变和搭便车中性突变的快速更替对于在耐药性在传播链内演变的情况下推断结核病传播事件具有重大意义。本文的在线版本（doi：10.1186/s13059-014-0490-3）包含补充材料，可供授权用户使用。
Mycobacterium tuberculosis is characterized by a low mutation rate and a lack of genetic recombination. Yet, the rise of extensively resistant strains paints a picture of a microbe with an impressive adaptive potential. Here we describe the first documented case of extensively drug-resistant tuberculosis evolved from a susceptible ancestor within a single patient. Genome sequences of nine serial M. tuberculosis isolates from the same patient uncovered a dramatic turnover of competing lineages driven by the emergence, and subsequent fixation or loss of single nucleotide polymorphisms. For most drugs, resistance arose through independent emergence of mutations in more than one clone, of which only one ultimately prevailed as the clone carrying it expanded, displacing the other clones in the process. The vast majority of mutations identified over 3.5 years were either involved in drug resistance or hitchhiking in the genetic background of these. Additionally, RNA-sequencing of isolates grown in the absence of drug challenge revealed that the efflux-associated iniBAC operon was up-regulated over time, whereas down-regulated genes include those involved in mycolic acid synthesis. We observed both rapid acquisitions of resistance to antimicrobial compounds mediated by individual mutations as well as a gradual increase in fitness in the presence of antibiotics, likely driven by stable gene expression reprogramming. The rapid turnover of resistance mutations and hitchhiking neutral mutations has major implications for inferring tuberculosis transmission events in situations where drug resistance evolves within transmission chains. The online version of this article (doi:10.1186/s13059-014-0490-3) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
3.7
作者：
Chatterjee A;Saranath D;Bhatter P;Mistry N
通讯作者：
Mistry N
影响因子：
4.2
作者：
Ballif M;Harino P;Ley S;Coscolla M;Niemann S;Carter R;Coulter C;Borrell S;Siba P;Phuanukoonnon S;Gagneux S;Beck HP
通讯作者：
Beck HP
影响因子：
3.7
作者：
Merker M;Kohl TA;Roetzer A;Truebe L;Richter E;Rüsch-Gerdes S;Fattorini L;Oggioni MR;Cox H;Varaine F;Niemann S
通讯作者：
Niemann S
DOI：
10.1073/pnas.0505446102
发表时间：
2005-08-23
影响因子：
11.1
作者：
Morris, RP;Nguyen, L;Thompson, CJ
通讯作者：
Thompson, CJ
影响因子：
4.9
作者：
An, Duong Duy;Duyen, Nguyen Thi Hong;Caws, Maxine
通讯作者：
Caws, Maxine