ArticleNucleic acids research2023
SigH stress response mediates killing of Mycobacterium tuberculosis by activating nitronaphthofuran prodrugs via induction of Mrx2 expression.
Article in Nucleic acids research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
5 citing papers in PubMed, 10 citations in OpenAlex.
- Host oxidative stress primes mycobacteria for rapid antibiotic resistance evolution.Nature communications · 2026Article
- Host oxidative stress primes mycobacteria for rapid antibiotic resistance evolution.Research square · 2025Article
- Environmental fungi target thiol homeostasis to compete with Mycobacterium tuberculosis.PLoS biology · 2024Article
- Environmental sphagnum-associated fungi target thiol homeostasis to compete withbioRxiv : the preprint server for biology · 2024Article
- Antibacterial Prodrugs to Overcome Bacterial Antimicrobial Resistance.Pharmaceuticals (Basel, Switzerland) · 2024Review
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Authors and funding
17 authors at 8 institutions in 5 countries.
Funding
Abstract
The emergence of drug-resistant Mycobacterium tuberculosis strains highlights the need to discover anti-tuberculosis drugs with novel mechanisms of action. Here we discovered a mycobactericidal strategy based on the prodrug activation of selected chemical derivatives classified as nitronaphthofurans (nNFs) mediated by the coordinated action of the sigH and mrx2 genes. The transcription factor SigH is a key regulator of an extensive transcriptional network that responds to oxidative, nitrosative, and heat stresses in M. tuberculosis. The nNF action induced the SigH stress response which in turn induced the mrx2 overexpression. The nitroreductase Mrx2 was found to activate nNF prodrugs, killing replicating, non-replicating and intracellular forms of M. tuberculosis. Analysis of SigH DNA sequences obtained from spontaneous nNF-resistant M. tuberculosis mutants suggests disruption of SigH binding to the mrx2 promoter site and/or RNA polymerase core, likely promoting the observed loss of transcriptional control over Mrx2. Mutations found in mrx2 lead to structural defects in the thioredoxin fold of the Mrx2 protein, significantly impairing the activity of the Mrx2 enzyme against nNFs. Altogether, our work brings out the SigH/Mrx2 stress response pathway as a promising target for future drug discovery programs.
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Registered trials
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