Emergence of mmpT5 Variants during Bedaquiline Treatment of Mycobacterium intracellulare Lung Disease
Emergence of mmpT5 Variants during Bedaquiline Treatment of Mycobacterium intracellulare Lung Disease
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DOI：
10.1128/jcm.02087-16
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发表时间：
2017-02-01
影响因子：
9.4
通讯作者：
Wallace, Richard J., Jr.
中科院分区：
文献类型：
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作者：
Alexander, David C.;Vasireddy, Ravikiran;Wallace, Richard J., Jr.
贝达喹啉（BDQ）是一种靶向ATP合酶的二芳基喹啉抗生素，可有效治疗对常规药物不再有反应的结核分枝杆菌感染。在研究BDQ作为挽救治疗的标签外使用时，13例胞内分枝杆菌肺病患者中有7例最初出现微生物学应答，然后复发。治疗前和复发M分离株的全基因组比较在细胞内发现了以前未表征的基因座mmpT 5中的突变。初步分析表明mmpT 5和mmpR 5基因座之间存在相似性，这与M中的低水平BDQ抗性相关。结核这两个基因编码转录调节因子，并与mmpS 5-mmpL 5药物外排操纵子的直系同源物相邻。然而，MmpT 5属于TetR超家族，而MmpR 5是马尔R家族蛋白。靶向测序发现了所有7例复发病例（包括2例治疗前分离株）分离株中的非同义mmpT 5突变。相比之下，只有两个复发患者的分离株有ATP合酶亚基c（atpE），BDQ的主要目标的非同义变化。药敏测试表明，mmpT 5突变与BDQ和氯法齐明的MIC适度增加2至8倍相关，而一种atpE突变体显示BDQ的MIC增加50倍。贝达喹啉显示出治疗M.虽然mmpT 5基因突变是细胞内肺疾病的一个重要特征，但需要优化治疗方案以防止mmpT 5变体的出现和微生物复发。
Bedaquiline (BDQ), a diarylquinoline antibiotic that targets ATP synthase, is effective for the treatment of Mycobacterium tuberculosis infections that no longer respond to conventional drugs. While investigating the off-label use of BDQ as salvage therapy, seven of 13 patients with Mycobacterium intracellulare lung disease had an initial microbiological response and then relapsed. Whole-genome comparison of pretreatment and relapse isolates of M. intracellulare uncovered mutations in a previously uncharacterized locus, mmpT5. Preliminary analysis suggested similarities between mmpT5 and the mmpR5 locus, which is associated with low-level BDQ resistance in M. tuberculosis. Both genes encode transcriptional regulators and are adjacent to orthologs of the mmpS5-mmpL5 drug efflux operon. However, MmpT5 belongs to the TetR superfamily, whereas MmpR5 is a MarR family protein. Targeted sequencing uncovered nonsynonymous mmpT5 mutations in isolates from all seven relapse cases, including two pretreatment isolates. In contrast, only two relapse patient isolates had nonsynonymous changes in ATP synthase subunit c (atpE), the primary target of BDQ. Susceptibility testing indicated that mmpT5 mutations are associated with modest 2-to 8-fold increases in MICs for BDQ and clofazimine, whereas one atpE mutant exhibited a 50-fold increase in MIC for BDQ. Bedaquiline shows potential for the treatment of M. intracellulare lung disease, but optimization of treatment regimens is required to prevent the emergence of mmpT5 variants and microbiological relapse.