p38 MAPK and MDT-15 mediate SKN-1-dependent metformin-induced protection against mitis group streptococci in Caenorhabditis elegans.

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.

Key Findings

• Metformin pretreatment provides dose-dependent protection against mitis group streptococcal-derived hydrogen peroxide in Caenorhabditis elegans.
• The protective effect of metformin is mediated by activation of the oxidative stress response transcription factor SKN-1/NRF2.
• Activation of SKN-1 by metformin requires the p38 MAPK pathway and the transcription mediator complex protein MDT-15, with MDT-15 mediating SKN-1 activity independently of p38 MAPK.

Clinical Significance

Citation

Al Hatem Ali, Balasubramaniam Boopathi, Villhauer Alissaet al.. p38 MAPK and MDT-15 mediate SKN-1-dependent metformin-induced protection against mitis group streptococci in Caenorhabditis elegans. GeroScience. 2026-Jul-27.