Small Molecule Inhibitors of the Bacterioferritin (BfrB)-Ferredoxin (Bfd) Complex Kill Biofilm-Embedded Cells.

Bacteria depend on a well-regulated iron homeostasis to survive adverse environments. A key component of the iron homeostasis machinery is the compartmentalization of Fe in bacterioferritin and its subsequent mobilization as Fe to satisfy metabolic requirements. In Fe is compartmentalized in bacterioferritin (BfrB), and its mobilization to the cytosol requires binding of a ferredoxin (Bfd) to reduce the stored Fe and release the soluble Fe.

Mobilization of Iron Stored in Bacterioferritin Is Required for Metabolic Homeostasis in .

Iron homeostasis offers a significant bacterial vulnerability because pathogens obtain essential iron from their mammalian hosts, but host-defenses maintain vanishingly low levels of free iron. Although pathogens have evolved mechanisms to procure host-iron, these depend on well-regulated iron homeostasis. To disrupt iron homeostasis, our work has targeted iron mobilization from the iron storage protein bacterioferritin (BfrB) by blocking a required interaction with its cognate ferredoxin partner (Bfd).

Small Molecule Inhibitors of the BfrB-Bfd Interaction Decrease Pseudomonas aeruginosa Fitness and Potentiate Fluoroquinolone Activity.

The iron storage protein bacterioferritin (BfrB) is central to bacterial iron homeostasis. The mobilization of iron from BfrB, which requires binding by a cognate ferredoxin (Bfd), is essential to the regulation of cytosolic iron levels in P. aeruginosa.

Inhibiting the BfrB:Bfd interaction in Pseudomonas aeruginosa causes irreversible iron accumulation in bacterioferritin and iron deficiency in the bacterial cytosol.

Iron is an essential nutrient for bacteria but the reactivity of Fe and the insolubility of Fe present significant challenges to bacterial cells. Iron storage proteins contribute to ameliorating these challenges by oxidizing Fe using O and HO as electron acceptors, and by compartmentalizing Fe. Two types of iron-storage proteins coexist in bacteria, the ferritins (Ftn) and the heme-containing bacterioferritins (Bfr), but the reasons for their coexistence are largely unknown.