Bacteria encounter a variety of stressors, especially during infection, where they are exposed to high levels of oxidative stress generated by immune cells. Reactive oxygen species (ROS) cause oxidative damage by modifying proteins, lipids, and nucleic acids. In proteins, ROS oxidise thiol groups in cysteine and methionine residues, forming disulfide bonds and sulfonyl groups, which can inactivate proteins and disrupt essential cellular functions. This can result in cell death if not repaired. To survive oxidative stress, bacteria possess multiple pathways to address different types of oxidative damage.
In the periplasm, one system that mitigates oxidative damage is the disulfide bond (Dsb) proteins which can isomerise or reduce erroneous disulfide bonds and prevent sulfonylation of thiols. Recently, a structurally homologous system, the suppressor of copper sensitivity (Scs) proteins, has been described. Scs proteins contribute to bacterial tolerance under copper exposure, another type of stress used by immune cells which also generates oxidative damage. Both Dsb and Scs systems receive reducing power from membrane dithiol reductases, DsbD and ScsB, respectively. These dithiol reductases transfer electrons to their periplasmic substrates, enabling them to combat oxidative damage.
Recent evidence suggests there is potential functional overlap between these two systems, particularly in substrate specificity, although this remains largely unexplored. We demonstrate new interactions between DsbD and ScsB and their substrates in Klebsiella pneumoniae, suggesting that each protein may act on substrates traditionally associated with the other. This crosstalk between systems suggests a broader capability for DsbD and ScsB in maintaining redox balance under oxidative stress and hints at potential redundancy between these systems.