ArticleProceedings of the National Academy of Sciences of the United States of America2000
Treatment of Mycobacterium tuberculosis with antisense oligonucleotides to glutamine synthetase mRNA inhibits glutamine synthetase activity, formation of the poly-L-glutamate/glutamine cell wall structure, and bacterial replication.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2000. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 132 citations in OpenAlex.
- In Vitro Preclinical Evaluation of BPP-PNA Antisense Antibiotics: A Protocol for Efficacy, Safety, and Resistance Analysis.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Chemical strategies for antisense antibiotics.Chemical Society reviews · 2024Review
- A comparative analysis of peptide-delivered antisense antibiotics using diverse nucleotide mimics.RNA (New York, N.Y.) · 2024Article
- RNA-Based Vaccines and Therapeutics Against Intracellular Pathogens.Methods in molecular biology (Clifton, N.J.) · 2024Review
- Principle, application and challenges of development siRNA-based therapeutics against bacterial and viral infections: a comprehensive review.Frontiers in microbiology · 2024Review
- The pathogenic mechanism of Mycobacterium tuberculosis: implication for new drug development.Molecular biomedicine · 2022Review
- Review
- Human Kinase IGF1R/IR Inhibitor Linsitinib Controls the In Vitro and Intracellular Growth ofACS infectious diseases · 2022Article
- Deletion of Glutamine Synthetase Gene Disrupts the Survivability and Infectivity ofFrontiers in cellular and infection microbiology · 2021Article
- Identification of Mycobacterium tuberculosis Peptides in Serum Extracellular Vesicles from Persons with Latent Tuberculosis Infection.Journal of clinical microbiology · 2020Article
- RNA‑seq analyses of antibiotic resistance mechanisms in Serratia marcescens.Molecular medicine reports · 2019Article
- A New Antisense Phosphoryl Guanidine Oligo-2'-O-Methylribonucleotide Penetrates Into Intracellular Mycobacteria and Suppresses Target Gene Expression.Frontiers in pharmacology · 2019Article
- Advances in therapeutic bacterial antisense biotechnology.Applied microbiology and biotechnology · 2018Review
- Transcriptional Approach for Decoding the Mechanism ofFrontiers in microbiology · 2018Article
- Review
- Sirtuin-dependent reversible lysine acetylation of glutamine synthetases reveals an autofeedback loop in nitrogen metabolism.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Proteomic response of methicillin-resistant S. aureus to a synergistic antibacterial drug combination: a novel erythromycin derivative and oxacillin.Scientific reports · 2016Article
- The prrF-encoded small regulatory RNAs are required for iron homeostasis and virulence of Pseudomonas aeruginosa.Infection and immunity · 2015Article
- The conserved hypothetical protein Rv0574c is required for cell wall integrity, stress tolerance, and virulence of Mycobacterium tuberculosis.Infection and immunity · 2015Article
- Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
New antibiotics to combat the emerging pandemic of drug-resistant strains of Mycobacterium tuberculosis are urgently needed. We have investigated the effects on M. tuberculosis of phosphorothioate-modified antisense oligodeoxyribonucleotides (PS-ODNs) against the mRNA of glutamine synthetase, an enzyme whose export is associated with pathogenicity and with the formation of a poly-L-glutamate/glutamine cell wall structure. Treatment of virulent M. tuberculosis with 10 microM antisense PS-ODNs reduced glutamine synthetase activity and expression by 25-50% depending on whether one, two, or three different PS-ODNs were used and the PS-ODNs' specific target sites on the mRNA. Treatment with PS-ODNs of a recombinant strain of Mycobacterium smegmatis expressing M. tuberculosis glutamine synthetase selectively inhibited the recombinant enzyme but not the endogenous enzyme for which the mRNA transcript was mismatched by 2-4 nt. Treatment of M. tuberculosis with the antisense PS-ODNs also reduced the amount of poly-L-glutamate/glutamine in the cell wall by 24%. Finally, treatment with antisense PS-ODNs reduced M. tuberculosis growth by 0. 7 logs (1 PS-ODN) to 1.25 logs (3 PS-ODNs) but had no effect on the growth of M. smegmatis, which does not export glutamine synthetase nor possess the poly-L-glutamate/glutamine (P-L-glx) cell wall structure. The experiments indicate that the antisense PS-ODNs enter the cytoplasm of M. tuberculosis and bind to their cognate targets. Although more potent ODN technology is needed, this study demonstrates the feasibility of using antisense ODNs in the antibiotic armamentarium against M. tuberculosis.
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