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Updated: Jul 6, 2025

Assaying for Inorganic Polyphosphate in Bacteria
07:20

Assaying for Inorganic Polyphosphate in Bacteria

Published on: January 21, 2019

8.7K

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

Saurabh Chugh1, Prabhakar Tiwari1, Charu Suri1

  • 1Translational Health Science and Technology Institute, National Capital Region Biotech Science Cluster, Faridabad 121001, India.

Proceedings of the National Academy of Sciences of the United States of America
|January 3, 2024
PubMed

Insights

Inorganic polyphosphate (polyP) regulates Mycobacterium tuberculosis pathogenesis. Inhibiting Polyphosphate Kinase-1 (PPK-1) with raloxifene hydrochloride reduces virulence and enhances antibiotic efficacy.

Area of Science:

  • Microbiology
  • Molecular Biology
  • Biochemistry

Background:

  • Inorganic polyphosphate (polyP) synthesized by Polyphosphate Kinase-1 (PPK-1) is crucial for cellular processes.
  • PPK-1 and polyP play significant roles in the pathogenesis of *Mycobacterium tuberculosis* (Mtb).

Purpose of the Study:

  • To investigate the role of polyP and PPK-1 in Mtb lipid biosynthesis and pathogenesis.
  • To identify inhibitors of PPK-1 and evaluate their therapeutic potential against Mtb.

Main Methods:

  • Gene deletion of *ppk-1* in Mtb.
  • Analysis of Mtb lipid profiles (PDIMs, TDM).
  • Macrophage infection assays and mouse models.
  • Host RNA-seq analysis.
  • Target-based screening and molecular docking to identify PPK-1 inhibitors.
  • Combination therapy studies with existing anti-TB drugs.

Main Results:

  • Deletion of *ppk-1* led to transcriptional and metabolic reprogramming in Mtb.
  • Δ*ppk-1* Mtb exhibited reduced levels of virulence-associated lipids (PDIMs, TDM).
  • PolyP deficiency enhanced phagosome-lysosome fusion and attenuated Mtb growth in mice.
  • Host RNA-seq revealed altered immune signaling pathways.
  • Raloxifene hydrochloride was identified as a PPK-1 inhibitor.
  • Raloxifene hydrochloride potentiated the activity of isoniazid, bedaquiline, and pretomanid against Mtb and inhibited Mtb growth in vivo.

Conclusions:

  • PolyP is a key regulator of Mtb pathogenesis, influencing lipid biosynthesis and host-pathogen interactions.
  • PPK-1 is a promising drug target for Mtb.
  • Raloxifene hydrochloride demonstrates potential as an adjuvant therapy to combat Mtb infections.
Keywords:
Mycobacterium tuberculosisinorganic polyphosphatepathogenesistarget-based screeningvirulence-associated factors

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