Less is more: Enterobactin concentration dependency in copper tolerance and toxicity

PERALTA, DAIANA ROMINA; FARIZANO, JUAN VICENTE; BULACIO GIL, NATALIA; CORBALÁN, NATALIA SOLEDAD; POMARES, MARÍA FERNANDA; VINCENT, PAULA ANDREA; ADLER, CONRADO

Frontiers in Molecular Biosciences

Frontiers

Año: 2022 vol. 9

The ability of siderophores to play roles beyond iron acquisition has beenrecently proven for many of them and evidence continues to grow. An earlierwork showed that the siderophore enterobactin is able to increase coppertoxicity by reducing Cu2+ to Cu+, a form of copper that is more toxic to cells.Copper toxicity is multifaceted. It involves the formation of reactive oxygenspecies (ROS), mismetallation of enzymes and possibly other mechanisms.Given that we previously reported on the capacity of enterobactin toalleviate oxidative stress caused by various stressors other than copper, weconsidered the possibility that the siderophore could play a dual role regardingcopper toxicity. In this work, we show a bimodal effect of enterobactin oncopper toxicity (protective and harmful) which depends on the siderophoreconcentration. We found that the absence of enterobactin renderedEscherichia coli cells more sensitive to copper, due to the reduced ability ofthose cells to cope with the metal-generated ROS. Consistently, addition of lowconcentrations of the siderophore had a protective effect by reducing ROSlevels. We observed that in order to achieve this protection, enterobactin had toenter cells and be hydrolyzed in the cytoplasm. Further supporting the role ofenterobactin in oxidative stress protection, we found that both oxygen andcopper, induced the expression of the siderophore and also found that copperstrongly counteracted the well-known downregulation effect of iron onenterobactin synthesis. Interestingly, when enterobactin was present in highconcentrations, cells became particularly sensitive to copper most likely due tothe Cu2+ to Cu+ reduction, which increased the metal toxicity leading to celldeath.