美国哥伦比亚大学Saeed Tavazoie团队近期取得重要工作进展，他们针对聚合型耐药性细胞状态进行了识别和基因剖析。相关研究成果2024年11月6日在线发表于《自然》杂志上。

据介绍，耐药株细胞是一种罕见的表型变异，在通常致命的抗生素水平下存活下来，是清除细菌感染的主要障碍。然而，了解耐药株形成的精确生理状态和遗传基础一直是一个长期的挑战。

研究人员生成了大肠杆菌生长转变的高分辨率单细胞RNA图谱，该图谱揭示了来自不同遗传和生理模型的耐药株，收敛到与标准生长阶段不同的转录状态，而是表现出翻译缺陷的主要特征。

然后，研究人员使用超密集CRISPR干扰来确定，每个大肠杆菌基因如何在遗传模型中促进耐药性的形成。在影响较大的关键基因中，研究人员发现了编码高度保守蛋白酶的lon和特征较差的yqgE基因，其产物强烈调节饥饿后休眠和持续的时间。

总之，这一研究工作揭示了饥饿引发的耐药性背后的关键生理和遗传因素，这是针对顽固性细菌感染中的耐药性的关键一步。

附：英文原文

Title: Identification and genetic dissection of convergent persister cell states

Author: Blattman, Sydney B., Jiang, Wenyan, McGarrigle, E. Riley, Liu, Menghan, Oikonomou, Panos, Tavazoie, Saeed

Issue&Volume: 2024-11-06

Abstract: Persister cells, rare phenotypic variants that survive normally lethal levels of antibiotics, present a major barrier to clearing bacterial infections1. However, understanding the precise physiological state and genetic basis of persister formation has been a longstanding challenge. Here we generated a high-resolution single-cell2 RNA atlas of Escherichia coli growth transitions, which revealed that persisters from diverse genetic and physiological models converge to transcriptional states that are distinct from standard growth phases and instead exhibit a dominant signature of translational deficiency. We then used ultra-dense CRISPR interference3 to determine how every E. coli gene contributes to persister formation across genetic models. Among critical genes with large effects, we found lon, which encodes a highly conserved protease4, and yqgE, a poorly characterized gene whose product strongly modulates the duration of post-starvation dormancy and persistence. Our work reveals key physiologic and genetic factors that underlie starvation-triggered persistence, a critical step towards targeting persisters in recalcitrant bacterial infections.

DOI: 10.1038/s41586-024-08124-2

Source: https://www.nature.com/articles/s41586-024-08124-2