ArticleAntimicrobial agents and chemotherapy2016
Stringent Response Factors PPX1 and PPK2 Play an Important Role in Mycobacterium tuberculosis Metabolism, Biofilm Formation, and Sensitivity to Isoniazid In Vivo.
Article in Antimicrobial agents and chemotherapy, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
29 citing papers in PubMed, 40 citations in OpenAlex.
- Immunotherapy targeting drug-tolerant Mycobacterium tuberculosis persisters accelerates tuberculosis cure in preclinical models.The Journal of clinical investigation · 2026Article
- The identification Mycobacterium tuberculosis genes that modulate long term survival in the presence of rifampicin and streptomycin.Scientific reports · 2025Article
- Bidirectional two-sample Mendelian randomization reveals causal link between genetic blood metabolites and tuberculosis.AMB Express · 2025Article
- Targeting the bacterial stringent response to combat human pathogens.Frontiers in immunology · 2025Review
- An Update on Polyphosphate In Vivo Activities.Biomolecules · 2024Review
- Mycobacterial Biofilm: Mechanisms, Clinical Problems, and Treatments.International journal of molecular sciences · 2024Review
- Polyphosphate kinase-1 regulates bacterial and host metabolic pathways involved in pathogenesis ofProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Gallein potentiates isoniazid's ability to suppressFrontiers in microbiology · 2024Article
- A mosquito AgTRIO mRNA vaccine contributes to immunity against malaria.NPJ vaccines · 2023Article
- Polyphosphate kinase 1 is involved in formation, the morphology and ultramicrostructure of biofilm ofHeliyon · 2023Article
- Polyphosphate Kinase Is Required for the Processes of Virulence and Persistence in Acinetobacter baumannii.Microbiology spectrum · 2022Article
- Therapeutic efficacy of antimalarial drugs targeting DosRS signaling inScience translational medicine · 2022Article
- Polyphosphate Kinase 2 (PPK2) Enzymes: Structure, Function, and Roles in Bacterial Physiology and Virulence.International journal of molecular sciences · 2022Review
- An intranasal stringent response vaccine targeting dendritic cells as a novel adjunctive therapy against tuberculosis.Frontiers in immunology · 2022Article
- Stringent Response in Mycobacteria: From Biology to Therapeutic Potential.Pathogens (Basel, Switzerland) · 2021Review
- Albumin fusion with granulocyte-macrophage colony-stimulating factor acts as an immunotherapy against chronic tuberculosis.Cellular & molecular immunology · 2021Article
- Targeting theFrontiers in microbiology · 2021Review
- Understanding the Reciprocal Interplay Between Antibiotics and Host Immune System: How Can We Improve the Anti-Mycobacterial Activity of Current Drugs to Better Control Tuberculosis?Frontiers in immunology · 2021Review
- Environmental pH is a key modulator of Staphylococcus aureus biofilm development under predation by the virulent phage phiIPLA-RODI.The ISME journal · 2021Article
- Tolerance and Persistence to Drugs: A Main Challenge in the Fight AgainstFrontiers in microbiology · 2020Review
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
Mycobacterium tuberculosis remains a global health threat largely due to the lengthy duration of curative antibiotic treatment, contributing to medical nonadherence and the emergence of drug resistance. This prolonged therapy is likely due to the presence of M. tuberculosis persisters, which exhibit antibiotic tolerance. Inorganic polyphosphate [poly(P)] is a key regulatory molecule in the M. tuberculosis stringent response mediating antibiotic tolerance. The polyphosphate kinase PPK1 is responsible for poly(P) synthesis in M. tuberculosis, while the exopolyphosphatases PPX1 and PPX2 and the GTP synthase PPK2 are responsible for poly(P) hydrolysis. In the present study, we show by liquid chromatography-tandem mass spectrometry that poly(P)-accumulating M. tuberculosis mutant strains deficient in ppx1 or ppk2 had significantly lower intracellular levels of glycerol-3-phosphate (G3P) and 1-deoxy-xylulose-5-phosphate. Real-time PCR revealed decreased expression of genes in the G3P synthesis pathway in each mutant. The ppx1-deficient mutant also showed a significant accumulation of metabolites in the tricarboxylic acid cycle, as well as altered arginine and NADH metabolism. Each poly(P)-accumulating strain showed defective biofilm formation, while deficiency of ppk2 was associated with increased sensitivity to plumbagin and meropenem and deficiency of ppx1 led to enhanced susceptibility to clofazimine. A DNA vaccine expressing ppx1 and ppk2, together with two other members of the M. tuberculosis stringent response, M. tuberculosis rel and sigE, did not show protective activity against aerosol challenge with M. tuberculosis, but vaccine-induced immunity enhanced the killing activity of isoniazid in a murine model of chronic tuberculosis. In summary, poly(P)-regulating factors of the M. tuberculosis stringent response play an important role in M. tuberculosis metabolism, biofilm formation, and antibiotic sensitivity in vivo.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.