Investigation of Zur-regulated metal transport systems reveals an unexpected role of pyochelin in zinc homeostasis.

Unlabelled: Limiting the availability of transition metals at infection sites serves as a critical defense mechanism employed by the innate immune system to combat microbial infections. exhibits a remarkable ability to thrive in zinc-deficient environments, facilitated by intricate cellular responses governed by numerous genes regulated by the zinc-responsive transcription factor Zur. Many of these genes have unknown functions, including those within the predicted and operons. A structural bioinformatics investigation revealed that comprises a TonB-dependent outer membrane receptor and inner membrane ABC-permeases responsible for importing metal-chelating molecules, whereas contains genes encoding a MacB transporter, likely involved in the export of large molecules. Molecular genetics and biochemical experiments, feeding assays, and intracellular metal content measurements support the hypothesis that and are engaged in the import and export of the pyochelin-cobalt complex, respectively. Notably, cobalt can reduce zinc demand and promote the growth of strains unable to import zinc, highlighting pyochelin-mediated cobalt import as a novel bacterial strategy to counteract zinc deficiency. These results unveil an unexpected role for pyochelin in zinc homeostasis and challenge the traditional view of this metallophore exclusively as an iron transporter.

Importance: The mechanisms underlying the remarkable ability of to resist the zinc sequestration mechanisms implemented by the vertebrate innate immune system to control bacterial infections are still far from being fully understood. This study reveals that the Zur-regulated gene clusters and encode systems for the import and export of cobalt-bound pyochelin, respectively. This proves to be a useful strategy to counteract conditions of severe zinc deficiency since cobalt can replace zinc in many proteins. The discovery that pyochelin may contribute to cellular responses to zinc deficiency leads to a reevaluation of the paradigm that pyochelin is a siderophore involved exclusively in iron acquisition and suggests that this molecule has a broader role in modulating the homeostasis of multiple metals.