Hu Minghao, Fu Lei, Wang Bin, Xu Jian, Guo Shaochen, Zhao Jiaojie, Li Yuanyuan, Chen Xiaoyou, Lu Yu
Department of Pharmacology, Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing 101149, People's Republic of China.
Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, People's Republic of China.
Infect Drug Resist. 2020 Jun 12;13:1751-1761. doi: 10.2147/IDR.S257145. eCollection 2020.
Linezolid (LZD) and pretomanid (PA-824) are promising candidates in regimens for the treatment of drug-resistant tuberculosis. However, research on LZD and PA-824 dual drug-resistant (LPDR) strains is rarely reported. This study aimed to investigate the genotypic and virulence characteristics of LPDR strains.
To obtain the LPDR strains (marked as LP or PL strains), we used a two-way induction method, namely, we first induced LZD- or PA-824-resistant mutants from the parental (MTB) strain H37Rv in vitro, then we obtained the LPDR strains from induction of LZD- or PA-824-resistant mutants. Mutations in , or and were identified in all mutants. To investigate the virulence of these strains, six strains were selected as representative strains, including LZD-resistant strains, PA-824-resistant strains and LPDR strains. We performed the animal survival study as virulence of MTB can be measured as survival time of an animal after being infected.
We induced 38 mutant strains of LZD and PA-824 mono or dual drug resistance from H37Rv in vitro. The mutation frequency of (C154R) gene in LPDR strains was 100% and 86%, respectively. In the animal survival study, animals infected with different drug-resistant strains survived significantly longer than those infected with H37Rv; animals infected with LPDR strains and PA-824-resistant strains survived similarly and both of which survived significantly shorter than those infected with LZD-resistant strains.
Our study showed that gene had a high mutation frequency in LPDR strains. The virulence of LPDR strains was similar to PA-824-resistant strains, and the virulence of the LZD-resistant strains was weaker than PA-824-resistant strains.
利奈唑胺（LZD）和普瑞马尼德（PA - 824）是治疗耐药结核病方案中很有前景的候选药物。然而，关于LZD和PA - 824双重耐药（LPDR）菌株的研究鲜有报道。本研究旨在调查LPDR菌株的基因型和毒力特征。
为获得LPDR菌株（标记为LP或PL菌株），我们采用双向诱导法，即首先在体外从亲本结核分枝杆菌（MTB）菌株H37Rv诱导出对LZD或PA - 824耐药的突变体，然后从LZD或PA - 824耐药突变体诱导获得LPDR菌株。在所有突变体中鉴定rpoB、katG或rpoB和katG中的突变。为研究这些菌株的毒力，选择6株作为代表性菌株，包括LZD耐药菌株、PA - 824耐药菌株和LPDR菌株。我们进行了动物存活研究，因为MTB的毒力可以通过动物感染后的存活时间来衡量。
我们在体外从H37Rv诱导出38株LZD和PA - 824单药或双药耐药的突变菌株。LPDR菌株中rpoB（C154R）基因的突变频率分别为100%和86%。在动物存活研究中，感染不同耐药菌株的动物存活时间明显长于感染H37Rv的动物；感染LPDR菌株和PA - 824耐药菌株的动物存活情况相似，且两者存活时间均明显短于感染LZD耐药菌株的动物。
我们的研究表明，rpoB基因在LPDR菌株中具有高突变频率。LPDR菌株的毒力与PA - 824耐药菌株相似，且LZD耐药菌株的毒力弱于PA - 824耐药菌株。
