MtrA modulates Mycobacterium tuberculosis cell division in host microenvironments to mediate intrinsic resistance and drug tolerance.
MtrA modulates Mycobacterium tuberculosis cell division in host microenvironments to mediate intrinsic resistance and drug tolerance.
复制标题
DOI：
10.1016/j.celrep.2023.112875
复制
发表时间：
2023-08-29
期刊：
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
结核分枝杆菌(Mtb)的成功很大程度上归功于它在生理上适应和抵抗宿主微环境中不同局部压力的能力。在这里，我们提出了一个数据驱动的模型(EGrin 2.0)，该模型捕获了环境线索和MTB中基因组编码的调控程序的动态相互作用。对EGrin 2.0的分析表明，MtrAB双组分信号系统的调节如何调节Mtb的生长，以响应相关的宿主微环境线索。通过可调CRISPR干扰对MtrAB的干扰证实，信号系统调节多种肽聚糖水解酶，以及其他靶点，这些酶对细胞分裂是重要的。此外，MTRA通过内在耐药和耐药机制降低抗生素的有效性。总之，对复杂的MTRA调控的模型启用的剖析突出了其作为药物靶标的重要性，并说明了EGrin 2.0如何促进Mtb适应宿主内特定宿主微环境的发现和机制表征。结核分枝杆菌EGrin 2.0描述了MtrAB如何在特定环境中调节结核分枝杆菌的细胞分裂MtrAB调节对结核分枝杆菌药物的内在耐药性和耐受性MTRA对结核分枝杆菌药物开发也是必不可少的，使其成为结核病药物开发的重要靶点结核分枝杆菌(Mtb)的成功源于其适应宿主内复杂和变化的微环境的能力。Peterson等人。开发一个EGrin 2.0模型，以促进探索在特定宿主微环境中工作的条件性基因调控和药物靶点。
The success of Mycobacterium tuberculosis (Mtb) is largely attributed to its ability to physiologically adapt and withstand diverse localized stresses within host microenvironments. Here, we present a data-driven model (EGRIN 2.0) that captures the dynamic interplay of environmental cues and genome-encoded regulatory programs in Mtb. Analysis of EGRIN 2.0 shows how modulation of the MtrAB two-component signaling system tunes Mtb growth in response to related host microenvironmental cues. Disruption of MtrAB by tunable CRISPR interference confirms that the signaling system regulates multiple peptidoglycan hydrolases, among other targets, that are important for cell division. Further, MtrA decreases the effectiveness of antibiotics by mechanisms of both intrinsic resistance and drug tolerance. Together, the model-enabled dissection of complex MtrA regulation highlights its importance as a drug target and illustrates how EGRIN 2.0 facilitates discovery and mechanistic characterization of Mtb adaptation to specific host microenvironments within the host. EGRIN 2.0 models environmental context-specific gene regulation in M. tuberculosis EGRIN 2.0 delineates how MtrAB tunes Mtb cell division in specific environments MtrAB regulation confers intrinsic resistance to and tolerance of anti-TB drugs MtrA is also essential for Mtb, making it an important target for TB drug development The success of Mycobacterium tuberculosis (Mtb) emerges from its capability to adapt to complex and varying microenvironments within the host. Peterson et al. develop an EGRIN 2.0 model to facilitate exploration of conditional gene regulation and drug targets that operate in specific host microenvironments.
登录
查看更多内容
影响因子：
4.2
作者：
Machowski EE;Senzani S;Ealand C;Kana BD
通讯作者：
Kana BD
影响因子：
6.7
作者：
Chao, Michael C.;Kieser, Karen J.;Rubin, Eric J.
通讯作者：
Rubin, Eric J.
影响因子：
64.5
作者：
Bonneau, Richard;Facciotti, Marc T.;Baliga, Nitin S.
通讯作者：
Baliga, Nitin S.
APRABC：结核分枝杆菌的复杂特异性基因座，可调节pH驱动的巨噬细胞吞噬体。
影响因子：
3.6
作者：
Abramovitch RB;Rohde KH;Hsu FF;Russell DG
通讯作者：
Russell DG
影响因子：
14.9
作者：
Neal ML;Wei L;Peterson E;Arrieta-Ortiz ML;Danziger SA;Baliga NS;Kaushansky A;Aitchison JD
通讯作者：
Aitchison JD