Identification of a new mycobacterial peptide that controls the activity of the iron-dependent regulator, IdeR

Mycobacterium tuberculosis ( Mtb ) must regulate intracellular iron to survive in the host and cause disease. IdeR ( I ron- de pendent R egulator) is an essential Mtb protein that governs intracellular iron levels by regulating the expression of genes involved in iron metabolism. IdeR expression, however, is iron independent, and the mechanisms that regulate IdeR’s function are not fully understood. Here, we report the discovery of a previously unrecognized Mtb peptide (PRI) that regulates IdeR activity. PRI is induced under iron limitation; it binds to IdeR and restricts its activity. In addition, we demonstrate that altering the balance between PRI and IdeR impairs iron homeostasis and intracellular replication of Mtb in macrophages. The findings reveal a new paradigm in mycobacterial iron regulation and open new avenues for targeting iron homeostatic mechanisms in Mtb , which are crucial for virulence and antibiotic resistance.