Copper-Mediated Antimicrobial Activity : Targeting Cytochrome c Complexes Across Bacterial Species

Copper (Cu) demonstrates strong antimicrobial properties and aids the immune system of mammals. While Cu in a dissolved state targets 4Fe-4S clusters in cytoplasmic dehydrogenases, its chemical reactivity and distribution imply that other cellular processes may also be susceptible to copper toxicity. Researchers have now discovered that c-type cytochrome biogenesis is a highly conserved target of excess Cu across various pathogenic and environmental bacteria.

When examining respiratory membrane complexes from pathogens like Vibrio cholerae and Pseudomonas aeruginosa, they found that these bacteria were highly sensitive to excess Cu, particularly when it comes to complexes containing c-type cytochromes. In P. aeruginosa, elevating Cu levels disrupted the cbb3-type cytochrome c oxidase and NapBC-containing cytochrome c complexes, while leaving complexes not dependent on c-type cytochromes, such as the aa3-type cytochrome c oxidase and succinate dehydrogenase, relatively unaffected.

Meanwhile, Bacillus subtilis, which has a covalently linked cytochrome c subunit in its caa3-type cytochrome c oxidase, also showed severe vulnerability to Cu. The same effect was observed in plant-associated and photosynthetic bacteria, suggesting that this susceptibility is widespread. By studying B. subtilis and Escherichia coli, the team found that Cu primarily interferes with the assembly of c-type cytochromes, rather than causing the breakdown of preassembled complexes.

These findings highlight c-type cytochrome-containing respiratory complexes as universally vulnerable targets of Cu toxicity. Being essential components of electron transport and adaptation to oxygen-poor conditions, the disruption of cytochrome c biogenesis may contribute to Cu's antimicrobial effects and expose a potential weak point in pathogens that depend on c-type cytochromes for microaerobic respiration and colonization of hypoxic host tissues.