气候变化领域集成服务门户(CCPortal): Phosphoenolpyruvate depletion mediates both growth arrest and drug tolerance of Mycobacterium tuberculosis in hypoxia

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DOI	10.1073/pnas.2105800118
	Phosphoenolpyruvate depletion mediates both growth arrest and drug tolerance of Mycobacterium tuberculosis in hypoxia
	Lim J.; Lee J.J.; Lee S.-K.; Kim S.; Eum S.-Y.; Eoh H.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:35
英文摘要	Mycobacterium tuberculosis (Mtb) infection is difficult to treat because Mtb spends the majority of its life cycle in a nonreplicating (NR) state. Since NR Mtb is highly tolerant to antibiotic effects and can mutate to become drug resistant (DR), our conventional tuberculosis (TB) treatment is not effective. Thus, a novel strategy to kill NR Mtb is required. Accumulating evidence has shown that repetitive exposure to sublethal doses of antibiotics enhances the level of drug tolerance, implying that NR Mtb is formed by adaptive metabolic remodeling. As such, metabolic modulation strategies to block the metabolic remodeling needed to form NR Mtb have emerged as new therapeutic options. Here, we modeled in vitro NR Mtb using hypoxia, applied isotope metabolomics, and revealed that phosphoenolpyruvate (PEP) is nearly completely depleted in NR Mtb. This near loss of PEP reduces PEP-carbon flux toward multiple pathways essential for replication and drug sensitivity. Inversely, supplementing with PEP restored the carbon flux and the activities of the foregoing pathways, resulting in growth and heightened drug susceptibility of NR Mtb, which ultimately prevented the development of DR. Taken together, PEP depletion in NR Mtb is associated with the acquisition of drug tolerance and subsequent emergence of DR, demonstrating that PEP treatment is a possible metabolic modulation strategy to resensitize NR Mtb to conventional TB treatment and prevent the emergence of DR. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Drug tolerance; Metabolic remodeling; Phosphoenolpyruvate; Synthetic lethality; Tuberculosis
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/238415
作者单位	Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, United States; Division of Immunology and Cellular Immunology, International Tuberculosis Research Center, Changwon, 51755, South Korea
推荐引用方式 GB/T 7714	Lim J.,Lee J.J.,Lee S.-K.,et al. Phosphoenolpyruvate depletion mediates both growth arrest and drug tolerance of Mycobacterium tuberculosis in hypoxia[J],2021,118(35).
APA	Lim J.,Lee J.J.,Lee S.-K.,Kim S.,Eum S.-Y.,&Eoh H..(2021).Phosphoenolpyruvate depletion mediates both growth arrest and drug tolerance of Mycobacterium tuberculosis in hypoxia.Proceedings of the National Academy of Sciences of the United States of America,118(35).
MLA	Lim J.,et al."Phosphoenolpyruvate depletion mediates both growth arrest and drug tolerance of Mycobacterium tuberculosis in hypoxia".Proceedings of the National Academy of Sciences of the United States of America 118.35(2021).