Polyphosphate kinase-1 regulates bacterial and host metabolic pathways involved in pathogenesis of Mycobacterium tuberculosis

• 成果类型: Article
• 署名作者: Chugh, Saurabh; Tiwari, Prabhakar; Suri, Charu; Gupta, Sonu Kumar; Singh, Padam; Bouzeyen, Rania; Kidwai, Saqib; Srivastava, Mitul; Rameshwaram, Nagender Rao; Kumar, Yashwant; Asthana, Shailendra; Singh, Ramandeep
• 署名单位: Department of Biotechnology (DBT) India; Translational Health Science & Technology Institute (THSTI); Pasteur Network; Universite de Tunis-El-Manar; Institut Pasteur Tunis
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14723
• DOI: 10.1073/pnas.2309664121
• 发表日期: 2024-01-09
• 关键词: inorganic polyphosphate; trehalose biosynthesis; acid biosynthesis; atp glucokinase; ppk2; purification; mechanisms; survival; insights; synthase

摘要

Inorganic polyphosphate (polyP) is primarily synthesized by Polyphosphate Kinase-1 (PPK-1) and regulates numerous cellular processes, including energy metabolism, stress adaptation, drug tolerance, and microbial pathogenesis. Here, we report that polyP interacts with acyl CoA carboxylases, enzymes involved in lipid biosynthesis in Mycobacterium tuberculosis. We show that deletion of ppk-1 in M. tuberculosis results in transcriptional and metabolic reprogramming. In comparison to the parental strain, the Delta ppk- 1 mutant strain had reduced levels of virulence-associated lipids such as PDIMs and TDM. We also observed that polyP deficiency in M. tuberculosis is associated with enhanced phagosome-lysosome fusion in infected macrophages and attenuated growth in mice. Host RNA-seq analysis revealed decreased levels of transcripts encoding for pro-teins involved in either type I interferon signaling or formation of foamy macrophages in the lungs of Delta ppk- 1 mutant-infected mice relative to parental strain-infected ani-mals. Using target-based screening and molecular docking, we have identified raloxifene hydrochloride as a broad- spectrum PPK-1 inhibitor. We show that raloxifene hydro-chloride significantly enhanced the activity of isoniazid, bedaquiline, and pretomanid against M. tuberculosis in macrophages. Additionally, raloxifene inhibited the growth of M. tuberculosis in mice. This is an in-depth study that provides mechanistic insights into the regulation of mycobacterial pathogenesis by polyP deficiency.