A comprehensive characterization of PncA polymorphisms that confer resistance to pyrazinamide.
A comprehensive characterization of PncA polymorphisms that confer resistance to pyrazinamide.
复制标题
DOI：
10.1038/s41467-017-00721-2
复制
发表时间：
2017-09-19
影响因子：
16.6
通讯作者：
Pym AS
中科院分区：
文献类型：
--
作者：
Yadon AN;Maharaj K;Adamson JH;Lai YP;Sacchettini JC;Ioerger TR;Rubin EJ;Pym AS
结核病化疗依赖于抗生素吡嗪酰胺的使用，而吡嗪酰胺正受到新出现的耐药性的威胁。耐药性是通过细菌基因pncA的突变介导的。用于测试吡嗪酰胺敏感性的方法是困难的并且很少执行，并且这意味着赋予吡嗪酰胺临床抗性的pncA等位基因的全谱是未知的。在这里，我们对pncA进行了体外饱和突变，以生成由单核苷酸多态性产生的PncA多态性的综合库。然后，我们在体外和感染的动物模型中筛选其吡嗪酰胺抗性。我们确定了超过300种赋予耐药性的取代。引人注目的是，这些突变映射到整个PncA结构，并导致酶活性的丧失和/或蛋白质丰度的降低。我们的综合突变和筛选方法应作为确定耐药突变及其作用机制的范例。抗生素吡嗪酰胺是全球结核病治疗方案的核心。尽管它的疗效，抗药性正在增加。在这里，Eric Rubin和他的同事研究了吡嗪酰胺耐药性的遗传基础。
Tuberculosis chemotherapy is dependent on the use of the antibiotic pyrazinamide, which is being threatened by emerging drug resistance. Resistance is mediated through mutations in the bacterial gene pncA. Methods for testing pyrazinamide susceptibility are difficult and rarely performed, and this means that the full spectrum of pncA alleles that confer clinical resistance to pyrazinamide is unknown. Here, we performed in vitro saturating mutagenesis of pncA to generate a comprehensive library of PncA polymorphisms resultant from a single-nucleotide polymorphism. We then screened it for pyrazinamide resistance both in vitro and in an infected animal model. We identify over 300 resistance-conferring substitutions. Strikingly, these mutations map throughout the PncA structure and result in either loss of enzymatic activity and/or decrease in protein abundance. Our comprehensive mutational and screening approach should stand as a paradigm for determining resistance mutations and their mechanisms of action. The antibiotic pyrazinamide is central to tuberculosis treatment regimens, globally. Despite its efficacy, resistance to the drug is increasing. Here, Eric Rubin and colleagues characterise the genetic basis of pyrazinamide resistance.
登录
查看更多内容
影响因子：
6.4
作者：
Bielecka MK;Tezera LB;Zmijan R;Drobniewski F;Zhang X;Jayasinghe S;Elkington P
通讯作者：
Elkington P
影响因子：
4.9
作者：
Chang, Kwok-Chiu;Leung, Chi-Chiu;Zhang, Ying
通讯作者：
Zhang, Ying
影响因子：
4.9
作者：
Hickey, MJ;Arain, TM;Stover, CK
通讯作者：
Stover, CK
DOI：
10.5588/ijtld.13.0195
发表时间：
2013-11-01
影响因子：
4
作者：
Hoffner, S.;Angeby, K.;Werngren, J.
通讯作者：
Werngren, J.
影响因子：
3.2
作者：
Meinzen, Christopher;Proano, Alvaro;Sheen, Patricia
通讯作者：
Sheen, Patricia