Phosphoenolpyruvate depletion mediates both growth arrest and drug tolerance of Mycobacterium tuberculosis in hypoxia

• DOI: 10.1073/pnas.2105800118
• Publication Date: 2021-08-23T20:27:58Z
• Authors: Juhyeon Lim; Jae Jin Lee; Sun-Kyung Lee; Seoyong Kim; Seok-Yong Eum; Hyungjin Eoh
• Keywords: Phosphoenolpyruvate; 0303 health sciences; 03 medical and health sciences; Antitubercular Agents; Humans; Tuberculosis; Drug Resistance, Microbial; Drug Tolerance; Mycobacterium tuberculosis; Hypoxia; 3. Good health

Significance

Nonreplicating (NR) Mycobacterium tuberculosis (Mtb) was thought to be drug tolerant due to its low metabolic activity. However, drug tolerance often gradually increases by exposure to antibiotics, inferring the role of an adaptive strategy. This study established that drug tolerance of NR Mtb is associated with phosphoenolpyruvate (PEP) anabolic down-regulation. PEP is a substrate of multiple pathways needed for replication; in NR Mtb, their functions were abolished due to PEP depletion. Intriguingly, PEP supplementation partly restored drug sensitivity and prevented the emergence of drug resistance (DR). The results expand our knowledge of how NR Mtb remodels its metabolic networks and propose potential Mtb metabolites as a source of therapeutic adjuvants to synthetically kill NR Mtb and prevent development of DR.