Phase variation in Mycobacterium tuberculosis glpK produces transiently heritable drug tolerance
Phase variation in Mycobacterium tuberculosis glpK produces transiently heritable drug tolerance
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DOI：
10.1073/pnas.1907631116
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发表时间：
2019-09-24
影响因子：
11.1
通讯作者：
Alland, David
中科院分区：
文献类型：
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作者：
Safi, Hassan;Gopal, Pooja;Alland, David
结核病（TB）治疗的时间和复杂性，以及结核分枝杆菌产生耐药性的倾向，是全球结核病控制工作的主要障碍。M.已知结核病能够进入耐药状态，这可以解释结核病治疗的许多障碍。我们已经确定了一个机制，遗传编码，但迅速可逆的药物耐受性在M。由glpK基因中7个胞嘧啶（7 C）的同聚体段（HT）中的瞬时移码突变引起的结核病。失活移码突变与7 C HT在glpK产生小菌落，表现出遗传性的多药最小抑制浓度的增加和减少药物依赖性杀伤;然而，逆转回一个完全药物敏感的大菌落表型发生迅速通过引入额外的插入或删除在相同的glpK HT区域。这些可逆的移码突变发生在M.结核分枝杆菌glpK存在于临床分离株中，在M.结核感染的小鼠在药物治疗过程中进一步积累，并表现出可逆的转录谱，包括诱导dosR和sigH和抑制kstR调节子，类似于在M.结核病耐受性这些结果表明，GlpK相位变异可能有助于人类TB的药物耐受性、治疗失败和复发。有效对抗相变M的药物。结核病可能加速结核病治疗并提高治愈率。
The length and complexity of tuberculosis (TB) therapy, as well as the propensity of Mycobacterium tuberculosis to develop drug resistance, are major barriers to global TB control efforts. M. tuberculosis is known to have the ability to enter into a drug-tolerant state, which may explain many of these impediments to TB treatment. We have identified a mechanism of genetically encoded but rapidly reversible drug tolerance in M. tuberculosis caused by transient frameshift mutations in a homopolymeric tract (HT) of 7 cytosines (7C) in the glpK gene. Inactivating frameshift mutations associated with the 7C HT in glpK produce small colonies that exhibit heritable multidrug increases in minimal inhibitory concentrations and decreases in drug-dependent killing; however, reversion back to a fully drug-susceptible large-colony phenotype occurs rapidly through the introduction of additional insertions or deletions in the same glpK HT region. These reversible frameshift mutations in the 7C HT of M. tuberculosis glpK occur in clinical isolates, accumulate in M. tuberculosis-infected mice with further accumulation during drug treatment, and exhibit a reversible transcriptional profile including induction of dosR and sigH and repression of kstR regulons, similar to that observed in other in vitro models of M. tuberculosis tolerance. These results suggest that GlpK phase variation may contribute to drug tolerance, treatment failure, and relapse in human TB. Drugs effective against phase-variant M. tuberculosis may hasten TB treatment and improve cure rates.