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Menadione reduces the expression of virulence- and colonization-associated genes in Helicobacter pylori
Stephen Thompson1, Omoyemi Rebecca Ojo1, Lesley Hoyles1
1School of Science and Technology, Nottingham Trent University, Nottingham, UK.
Abstract:
Novel treatment options are needed for the gastric pathogen Helicobacter pylori due to its increasing antibiotic resistance. The vitamin K analogue menadione has been extensively studied due to interest in its anti-bacterial and anti-cancer properties. Here, we investigated the effects of menadione on H. pylori growth, viability, antibiotic resistance, motility and gene expression using clinical isolates. The MIC of menadione was 313 µM for 11/13 isolates and 156 µM for 2/13 isolates. The minimum bactericidal concentrations were 1.25-2.5 mM, indicating that concentrations in the micromolar range were bacteriostatic rather than bactericidal. We were not able to experimentally evolve resistance to menadione in vitro. Sub-MIC menadione (16 µM for 24 h) did not significantly inhibit bacterial growth but significantly (P<0.05) changed the expression of 1291/1615 (79.9%) genes encoded by strain 322A. The expression of the virulence factor genes cagA and vacA was downregulated in the presence of sub-MIC menadione, while genes involved in stress responses were upregulated. Sub-MIC menadione significantly (P<0.0001) inhibited the motility of H. pylori, consistent with the predicted effects of the observed significant (P<0.05) downregulation of cheY, upregulation of rpoN and changes in the expression of flagellar assembly pathway genes seen in the transcriptomic analysis. Through in-depth interrogation of transcriptomic data, we concluded that sub-MIC menadione elicits a general stress response in H. pylori with survival in the stationary phase likely mediated by the upregulation of surE and rpoN. Sub-MIC menadione caused some modest increases in H. pylori susceptibility to antibiotics, but the effect was variable with strain and antibiotic type and did not reach statistical significance. Menadione (78 µM) was minimally cytotoxic to human gastric adenocarcinoma (AGS) cells after 4 h but caused a significant loss of cell viability after 24 h. Given its inhibitory effects on bacterial growth, motility and expression of virulence- and colonization-associated genes, menadione at low micromolar concentrations may have potential utility as a virulence-attenuating agent against H. pylori.
Insights
Menadione, a vitamin K analogue, shows potential against antibiotic-resistant Helicobacter pylori by inhibiting bacterial motility and virulence gene expression. While not bactericidal at low concentrations, it may serve as a virulence-attenuating agent.
Area of Science:
- Microbiology
- Infectious Diseases
- Drug Discovery
Background:
- Increasing antibiotic resistance in Helicobacter pylori necessitates novel treatment strategies.
- Menadione, a vitamin K analogue, possesses known anti-bacterial and anti-cancer properties.
- Previous research indicates interest in menadione's therapeutic potential.
Purpose of the Study:
- To investigate the effects of menadione on H. pylori growth, viability, and antibiotic resistance.
- To analyze menadione's impact on H. pylori gene expression and motility.
- To evaluate menadione's potential as a virulence-attenuating agent against H. pylori.
Main Methods:
- Determined minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC) of menadione for clinical H. pylori isolates.
- Assessed the effects of sub-inhibitory concentrations (sub-MIC) of menadione on bacterial growth, gene expression (transcriptomics), and motility.
- Investigated menadione's cytotoxicity on human gastric adenocarcinoma (AGS) cells.
Main Results:
- Menadione exhibited bacteriostatic effects at micromolar concentrations (MIC: 156-313 µM) and bactericidal effects at millimolar concentrations (MBC: 1.25-2.5 mM).
- Sub-MIC menadione significantly altered the expression of a large proportion of H. pylori genes, downregulating virulence factors (cagA, vacA) and upregulating stress response genes.
- Sub-MIC menadione significantly inhibited bacterial motility and showed minimal cytotoxicity to AGS cells at low concentrations.
Conclusions:
- Menadione at sub-MIC concentrations elicits a general stress response in H. pylori, potentially aiding survival.
- Menadione demonstrates potential as a virulence-attenuating agent by inhibiting motility and downregulating key virulence genes.
- Further research into menadione's therapeutic utility against H. pylori infections is warranted.
