어형진 (University of Southern California) | 한빛사논문 > 한빛사

한빛사논문

조회516

University of Southern California

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Proc. Natl. Acad. Sci. USA, August 31, 2021, 118 (35) : e2105800118 | https://doi.org/10.1073/pnas.2105800118 Phosphoenolpyruvate depletion mediates both growth arrest and drug tolerance of Mycobacterium tuberculosis in hypoxia

Juhyeon Lim^a, Jae Jin Lee^a, Sun-Kyung Lee^b, Seoyong Kim^a, Seok-Yong Eum^b, and Hyungjin Eoh^a,1

^aDepartment of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033; and ^bDivision of Immunology and Cellular Immunology, International Tuberculosis Research Center, Changwon 51755, Republic of Korea

¹To whom correspondence may be addressed.

Abstract

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.

tuberculosis, metabolic remodeling, drug tolerance, synthetic lethality, phosphoenolpyruvate

논문정보

형식Research article
게재일2021년 08월 (BRIC 등록일 2021-09-06)
연구진국내+국외 연구진
분야 생명과학 > 미생물학

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