Zinc excess impairs <i>Mycobacterium bovis</i> growth through triggering a Zur-IdeR-iron homeostasis signal pathway

Importance As a catalytic and structural cofactor of proteins, zinc is essential for almost all living organisms. However, zinc excess is toxic and represents a vital innate immunity strategy of macrophages to combat intracellular pathogens, especially against mycobacterial pathogens such as Mycobacterium tuberculosis , the causative agent of tuberculosis. Here, we first characterize an antibacterial signaling pathway of zinc excess and its relationship with iron homeostasis in M. bovis . We found that excess zinc inhibits the transcription of ideR and its DNA-binding activity through Zur, which, in turn, promotes the expression of iron uptake genes, causes intracellular iron accumulation, and finally impairs the bacterial growth. This study reveals the existence of the Zur-IdeR-iron homeostasis pathway triggered by zinc excess in M. bovis , which will shed light on the crosstalk mechanisms between zinc and iron homeostasis in bacteria and the antimicrobial mechanisms of host-mediated zinc toxicity.