通过 tRNA 突变激活抗生素的细菌持久性。

IF 3.9 2区 医学 Q1 INFECTIOUS DISEASES Journal of Antimicrobial Chemotherapy Pub Date : 2024-11-04 DOI:10.1093/jac/dkae307
Jongwook Park, Dongju Lee, Hyojeong Yi, Cheol-Won Yun, Heenam Stanley Kim
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引用次数: 0

摘要

目的:细菌持续存在是慢性感染和复发性感染难以治愈的一个重要原因。尽管其重要性不言而喻,但许多潜在机制仍不甚明了:方法:通过暴露于致死剂量的 AMP 或 MEM,分离出泰国伯克霍尔德氏菌的抗生素耐受突变体,然后进行全基因组测序以确定突变。随后,通过杀灭曲线、生长曲线和持续率图对这些突变体进行了全面鉴定。利用 Northern 印迹分析检测不带电的 tRNA,而 relA 和 spoT 空突变的产生则证实了严格反应参与了这种持续机制。通过将突变体在不使用抗生素的情况下培养 2 周,证明了持久性突变的表型逆转:结果:我们发现了由 tRNAAsp 反密码子环 32 或 38 位上的特定突变引发的一种新的持久性机制。这就通过一种依赖于 RelA 的严格反应提高了持久性。值得注意的是,当持续性不再是生存所必需时,通过丢失 tRNA 基因簇中的突变 tRNA 等位基因,这种持续性可以很容易地恢复到野生型生理状态:结论:这种独特形式的持续性强调了反密码子环内第 32 或 38 位 tRNA 突变的新功能,以及 tRNA 基因簇在赋予适应性以调节持续性从而提高存活率方面的重要性。
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Bacterial persistence to antibiotics activated by tRNA mutations.

Objectives: Bacterial persistence is a significant cause of the intractability of chronic and relapsing infections. Despite its importance, many of the underlying mechanisms are still not well understood.

Methods: Antibiotic-tolerant mutants of Burkholderia thailandensis were isolated through exposure to lethal doses of AMP or MEM, followed by whole-genome sequencing to identify mutations. Subsequently, these mutants underwent comprehensive characterization via killing curves, growth curves, and persistence-fraction plots. Northern blot analysis was employed to detect uncharged tRNA, while the generation of relA and spoT null mutations served to confirm the involvement of the stringent response in this persistence mechanism. Phenotypic reversion of the persistence mutation was demonstrated by incubating the mutants without antibiotics for 2 weeks.

Results: We have discovered a novel mechanism of persistence triggered by specific mutations at positions 32 or 38 within the anticodon loop of tRNAAsp. This leads to heightened persistence through a RelA-dependent stringent response. Notably, this persistence can be easily reverted to wild-type physiology by losing the mutant tRNA allele within the tRNA gene cluster when persistence is no longer essential for survival.

Conclusions: This distinct form of persistence underscores the novel function of tRNA mutations at positions 32 or 38 within the anticodon loop, as well as the significance of the tRNA gene cluster in conferring adaptability to regulate persistence for enhanced survival.

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来源期刊
CiteScore
9.20
自引率
5.80%
发文量
423
审稿时长
2-4 weeks
期刊介绍: The Journal publishes articles that further knowledge and advance the science and application of antimicrobial chemotherapy with antibiotics and antifungal, antiviral and antiprotozoal agents. The Journal publishes primarily in human medicine, and articles in veterinary medicine likely to have an impact on global health.
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