Despite inducing antioxidant regulation, superoxide dismutase deficiency makes Escherichia coli more sensitive to hydrogen peroxide.

Superoxide is a toxic byproduct of aerobic cellular respiration. The cellular regulation of bacterial responses to superoxide stress remains incompletely understood. The present work established an Escherichia coli cell model for superoxide stress by deleting superoxide dismutase (SOD) SodA and SodB. Proteomic analysis revealed that SOD deficiency not only induced high expression of the oxidative stress regulator SoxSR but also upregulated the catalase KatE and the organic peroxidases Tpx and BtuE, suggesting that SOD deficiency leads to the subsequent production of multiple reactive oxygen species. Further analysis of central carbon metabolism networks showed that SOD deficiency suppressed oxidative phosphorylation, thereby reducing superoxide production. SOD defects stimulated the pentose phosphate pathway (PPP) and its downstream pathways involved in histidine and phenylalanine synthesis, as well as fatty acid degradation pathway. SOD deficiency rendered E. coli more sensitive to the lethal effects of exogenous hydrogen peroxide. CRISPR-mediated deletion of zwf to block PPP, deletion of hisD and pheA to disrupt histidine and phenylalanine synthesis, or deletion of fadE to block fatty acid degradation, all increased the SOD mutant's sensitivity to hydrogen peroxide. The absence of fadE, rather than hisD or pheA, further reduced the survival of zwf-SOD mutant under H2O2 killing. These data indicate that the PPP and fatty acid degradation pathways help SOD-deficient cells respond to oxidative stress. Overall, our findings offer new perspectives on bacterial defenses against oxidative stress and survival strategies.