Metformin protects Escherichia coli from bleomycin-induced bactericide via enhanced generation of hydrogen peroxide

Bleomycin is a glycopeptide antibiotic that is widely employed in the therapy of a range of lymphomas and germ cell tumours. But the therapeutic efficacy of bleomycin is limited by development of lung fibrosis. The cytotoxicity of bleomycin is mostly ascribed to mitochondrial DNA (mtDNA) damage, while a protective effect of metformin against bleomycin-induced lung fibrosis results from the inhibition of mitochondrial complex I. Since mitochondria and bacteria have certain similarities in structure and function, we used Escherichia coli for simplification in the present work to investigate the relationship between metformin and bleomycin with apparently opposite effects on mitochondrial DNA damage. Bleomycin lethality to E. coli was ameliorated by metformin treatment accompanying further increase of the level of reactive oxygen species. Catalase but not superoxide dismutases attenuated the protective effect of metformin. Meanwhile, treatment with hydrogen peroxide enhanced the protection, indicating that metformin may protect E. coli from bleomycin-induced bactericide via enhanced generation of hydrogen peroxide. Moreover, silibinin, a hepatoprotective polyphenolic flavonoid attenuates the cytotoxicity of bleomycin to E. coli via enhanced generation of hydrogen peroxide as well. This bacterial model in place of mitochondria can provide us with easier screening for the molecules with capability of reducing the bleomycin side effect.