期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2105800118
关键词
tuberculosis; metabolic remodeling; drug tolerance; synthetic lethality; phosphoenolpyruvate
资金
- Donald E. & Delia Baxter Foun-dation
- L.K. Whittier Foundation
- Wright Foundation
- American Lung Association Innovative Award
- NIH [R21 AI139386, R56 AI143870]
- Korea Centers for Disease Control and Prevention, Republic of Korea
The nonreplicating state of Mycobacterium tuberculosis undergoes metabolic remodeling, with the depletion of phosphoenolpyruvate (PEP) leading to drug resistance, while supplementation with PEP restores drug sensitivity, preventing the emergence of drug-resistant strains.
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据