Genetic and Virulence Characteristics of Linezolid and Pretomanid Dual Drug -Resistant Strains Induced from Mycobacterium tuberculosis in vitro
Genetic and Virulence Characteristics of Linezolid and Pretomanid Dual Drug -Resistant Strains Induced from Mycobacterium tuberculosis in vitro
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DOI：
10.2147/idr.s257145
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发表时间：
2020-01-01
影响因子：
3.9
通讯作者：
Lu, Yu
中科院分区：
文献类型：
--
作者：
Hu, Minghao;Fu, Lei;Lu, Yu
目的：利奈唑胺（LZD）和pretomanid（PA-824）是治疗耐药结核病方案中有希望的候选药物。然而，关于LZD和PA-824双重耐药（LPDR）菌株的研究很少报道。本研究的目的是调查LPDR菌株的基因型和毒力特性。研究方法：为了获得LPDR菌株（标记为LP或PL菌株），我们使用双向诱导方法，即首先从亲本结核分枝杆菌（MTB）菌株H37 Rv体外诱导LZD或PA-824抗性突变体，然后通过诱导LZD或PA-824抗性突变体获得LPDR菌株。在所有突变体中鉴定了rplC、rrl或ddn和fgdl中的突变。为了研究这些菌株的毒力，选择了6个菌株作为代表菌株，包括LZD抗性菌株、PA-824抗性菌株和LPDR菌株。我们进行了动物存活研究，因为MTB的毒力可以测量为动物在感染后的存活时间。结果：体外诱导出38株LZD和PA-824单耐或双耐突变株。LPDR株rp 1C（C154 R）基因突变率分别为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H37 Rv的动物;感染LPDR菌株和PA-824耐药菌株的动物存活时间相似，且两者存活时间均明显短于感染LZD耐药菌株的动物。结论：本研究表明LPDR菌株中rplC基因突变频率较高。LPDR菌株的毒力与PA-824耐药菌株相似，而LZD耐药菌株的毒力弱于PA-824耐药菌株。
Purpose: 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. Methods: 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 Mycobacterium tuberculosis (MTB) strain H37Rv in vitro, then we obtained the LPDR strains from induction of LZD- or PA-824-resistant mutants. Mutations in rplC, rrl, or ddn and fgd1 were identified in all mutants. To investigate the virulence of these strains, six strains were selected as representative strains, including LZD-resistant strains, PA-824resistant 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. Results: We induced 38 mutant strains of LZD and PA-824 mono or dual drug resistance from H37Rv in vitro. The mutation frequency of rplC (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. Conclusion: Our study showed that rplC 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.