Lim Juhyeon, Lee Jae Jin, Lee Sun-Kyung, Kim Seoyong, Eum Seok-Yong, Eoh Hyungjin
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033.
Division of Immunology and Cellular Immunology, International Tuberculosis Research Center, Changwon 51755, Republic of Korea.
Proc Natl Acad Sci U S A. 2021 Aug 31;118(35). doi: 10.1073/pnas.2105800118.
(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.
结核分枝杆菌（Mtb）感染难以治疗，因为Mtb在其生命周期的大部分时间处于非复制（NR）状态。由于NR Mtb对抗生素作用具有高度耐受性，并且可能发生突变而产生耐药性（DR），我们传统的结核病（TB）治疗方法并不有效。因此，需要一种杀死NR Mtb的新策略。越来越多的证据表明，反复暴露于亚致死剂量的抗生素会提高耐药水平，这意味着NR Mtb是通过适应性代谢重塑形成的。因此，阻断形成NR Mtb所需的代谢重塑的代谢调节策略已成为新的治疗选择。在这里，我们利用缺氧在体外模拟NR Mtb，应用同位素代谢组学，并揭示磷酸烯醇丙酮酸（PEP）在NR Mtb中几乎完全耗尽。PEP的这种近乎丧失减少了PEP-碳向复制和药物敏感性所必需的多种途径的通量。相反，补充PEP恢复了碳通量和上述途径的活性，导致NR Mtb生长并提高了药物敏感性，最终防止了DR的发生。综上所述，NR Mtb中PEP的消耗与耐药性的获得以及随后DR的出现有关，这表明PEP治疗是一种可能的代谢调节策略，可使NR Mtb对传统TB治疗重新敏感并防止DR的出现。
