Dioxygen reductase heterogeneity is crucial for robust aerobic growth physiology of .

The development of a system to leverage molecular oxygen for energy-efficient pathways required several molecular adaptations. The enzymatic reduction of dioxygen to water is one such prominent evolutionary molecular trait. Microbes evolved several enzymes capable of reducing dioxygen and, interestingly, retained multiples of them in their genomes. While their structure and biochemical functions are well-studied, understanding their degeneracy and co-operativity in the system remains elusive. We used genetic engineering and evolutionary repair approaches to examine the impact of the high oxygen affinity cytochrome bd oxidase deficiency in Escherichia coli aerobic growth. We found a crucial role of cytochrome bd oxidases in the robustness of aerobic physiology. Evolutionary repair experiments alleviated growth defects in bd oxidase-deficient strains by ArcAB system dysregulation at the cost of impaired stress response pathways. Energy generation pathways are potential antimicrobial targets, and understanding collateral phenotypes is crucial in designing therapeutic approaches that reduce antimicrobial resistance development.