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Updated: Aug 5, 2026
Studying Oxidative Stress Caused by the Mitis Group Streptococci in Caenorhabditis elegans
Published on: March 23, 2019
p38 MAPK and MDT-15 mediate SKN-1-dependent metformin-induced protection against mitis group streptococci in
Ali Al Hatem1, Boopathi Balasubramaniam2, Alissa Villhauer2
1Department of Periodontics and Dental Hygiene, School of Dentistry, University of Texas Health Science Center, Houston, TX, USA.
Abstract:
Mitis group streptococci are opportunistic pathogens residing in the oral cavity, where they produce hydrogen peroxide (H2O2), a key virulence factor contributing to their pathogenesis. We previously demonstrated that these bacteria kill the nematode Caenorhabditis elegans through H2O2 production. Metformin, a widely used biguanide drug for managing blood glucose levels, has shown promising effects on aging by extending lifespan in worms and mice, and has also demonstrated potential cancer treatment. Additionally, pretreatment with metformin enhances the survival of worms and triggers an immune response via the p38 MAPK pathway against various pathogenic bacteria. Based on these observations, we investigated metformin's potential as a therapeutic agent against mitis group streptococcal infections and its underlying mechanisms in the current study. Pretreatment of worms with metformin provided significant dose-dependent protection from streptococcal-derived H2O2. This protective effect was attributed to the activation of the oxidative stress response transcription factor SKN-1/NRF2. Further analysis revealed that the p38 MAPK pathway and the transcription mediator complex protein MDT-15 are essential for the activation of SKN-1 by metformin. Interestingly, SKN-1 activity, mediated by MDT-15, was found to be independent of the p38 MAPK pathway. Our findings establish that metformin-mediated protection against mitis group streptococcal infections relies on the coordinated action of SKN-1, the p38 MAPK pathway, and MDT-15. These insights suggest that metformin could be a valuable therapeutic agent in combating these infections. Future research should focus on further elucidating the molecular mechanisms involved and exploring the potential clinical applications of metformin in treating these bacterial infections.
Insights
Metformin protects against oral streptococcal infections by activating the SKN-1 pathway, involving p38 MAPK and MDT-15. This suggests metformin
Area of Science:
- Microbiology
- Pathogenesis
- Pharmacology
Background:
- Mitis group streptococci are oral opportunistic pathogens producing hydrogen peroxide (H2O2), a virulence factor.
- Metformin, a diabetes drug, extends lifespan and shows anti-cancer potential.
- Metformin enhances worm survival against pathogens via the p38 MAPK pathway.
Purpose of the Study:
- Investigate metformin's therapeutic potential against mitis group streptococcal infections.
- Elucidate the underlying molecular mechanisms of metformin's protective effects.
Main Methods:
- Utilized Caenorhabditis elegans as a model organism.
- Assessed worm survival and protection against H2O2-producing streptococci.
- Analyzed the roles of SKN-1/NRF2, p38 MAPK pathway, and MDT-15 in metformin's action.
Main Results:
- Metformin pretreatment conferred dose-dependent protection against streptococcal H2O2.
- Protection was mediated by the activation of the oxidative stress response transcription factor SKN-1/NRF2.
- The p38 MAPK pathway and MDT-15 were essential for SKN-1 activation by metformin, with MDT-15 acting independently of p38 MAPK.
Conclusions:
- Metformin-mediated protection involves the coordinated action of SKN-1, p38 MAPK, and MDT-15.
- Metformin shows promise as a therapeutic agent for mitis group streptococcal infections.
- Further research is needed to explore clinical applications and detailed mechanisms.
