Inhibitors of the Bacterioferritin Ferredoxin Complex Dysregulate Iron Homeostasis and Kill and Biofilm-Embedded Cells.

In , the iron storage protein bacterioferritin (Bfr) contributes to buffering cytosolic free iron concentrations by oxidizing Fe and storing the resultant Fe in its internal cavity, and by forming a complex with a cognate ferredoxin (Bfd) to reduce the stored Fe and mobilize Fe to the cytosol. Small molecule derivatives of 4-aminoisoindoline-1,3-dione designed to bind Bfr (Pa Bfr) at the Bfd binding site accumulate in the cell, block the Pa Bfr-Bfd complex, inhibit iron mobilization from Pa Bfr, elicit an iron starvation response, are bacteriostatic to planktonic cells, and are bactericidal to biofilm-entrenched cells. A structural alignment of Pa Bfr and Bfr (Ab Bfr) showed strong conservation of the Bfd binding site on Ab Bfr. Accordingly, the small molecule inhibitors of the Pa Bfr-Bfd complex accumulate in the cells, elicit an iron starvation response, are bactericidal to planktonic cells, and exhibit synergy with existing antibiotics. These findings indicate that the inhibition of iron mobilization from Bfr may be an antimicrobial strategy applicable to other Gram-negative pathogens.