Ramirez-Busby Sarah M, Valafar Faramarz
Bioinformatics and Medical Informatics Research Center, San Diego State University, San Diego, California, USA.
Bioinformatics and Medical Informatics Research Center, San Diego State University, San Diego, California, USA
Antimicrob Agents Chemother. 2015 Sep;59(9):5267-77. doi: 10.1128/AAC.00204-15. Epub 2015 Jun 15.
Pyrazinamide (PZA) is an important first-line drug in the treatment of tuberculosis (TB) and of significant interest to the HIV-infected community due to the prevalence of TB-HIV coinfection in some regions of the world. The mechanism of resistance to PZA is unlike that of any other anti-TB drug. The gene pncA, encoding pyrazinamidase (PZase), is associated with resistance to PZA. However, because single mutations in PZase have a low prevalence, the individual sensitivities are low. Hundreds of distinct mutations in the enzyme have been associated with resistance, while some only appear in susceptible isolates. This makes interpretation of molecular testing difficult and often leads to the simplification that any PZase mutation causes resistance. This systematic review reports a comprehensive global list of mutations observed in PZase and its promoter region in clinical strains, their phenotypic association, their global frequencies and diversity, the method of phenotypic determination, their MIC values when given, and the method of MIC determination and assesses the strength of the association between mutations and phenotypic resistance to PZA. In this systematic review, we report global statistics for 641 mutations in 171 (of 187) codons from 2,760 resistant strains and 96 mutations from 3,329 susceptible strains reported in 61 studies. For diagnostics, individual mutations (or any subset) were not sufficiently sensitive. Assuming similar error profiles of the 5 phenotyping platforms included in this study, the entire enzyme and its promoter provide a combined estimated sensitivity of 83%. This review highlights the need for identification of an alternative mechanism(s) of resistance, at least for the unexplained 17% of cases.
吡嗪酰胺（PZA）是治疗结核病（TB）的一种重要一线药物，由于世界上某些地区结核分枝杆菌与人类免疫缺陷病毒（TB-HIV）合并感染的普遍性，它受到了HIV感染群体的极大关注。对PZA的耐药机制与任何其他抗结核药物都不同。编码吡嗪酰胺酶（PZase）的基因pncA与对PZA的耐药性有关。然而，由于PZase中的单个突变发生率较低，个体敏感性也较低。该酶中数百种不同的突变与耐药性有关，而有些突变仅出现在敏感菌株中。这使得分子检测的解读变得困难，并且常常导致任何PZase突变都会导致耐药性的简化结论。本系统评价报告了在临床菌株中PZase及其启动子区域观察到的突变的全面全球列表、它们的表型关联、全球频率和多样性、表型测定方法、给出时的最低抑菌浓度（MIC）值以及MIC测定方法，并评估了突变与对PZA的表型耐药性之间关联的强度。在本系统评价中，我们报告了61项研究中2760株耐药菌株的171个（共187个）密码子中的641个突变以及3329株敏感菌株中的96个突变的全球统计数据。对于诊断而言，单个突变（或任何子集）的敏感性不足。假设本研究中纳入的5个表型分析平台具有相似的误差特征，整个酶及其启动子的综合估计敏感性为83%。本综述强调了至少针对17%无法解释的病例，需要识别出替代的耐药机制。
