Mobilization of iron stored in bacterioferritin, a new target for perturbing iron homeostasis and developing antibacterial and antibiofilm molecules

Abstract

Antibiotic resistance is a global public health threat. The care of chronic infections is complicated by bacterial biofilms. Biofilm embedded cells can be up to 1000-fold more tolerant to antibiotic treatment than planktonic cells. Antibiotic tolerance is a condition which does not involve mutation and enables bacteria to survive in the presence of antibiotics. The antibiotic tolerance of biofilm-cells often renders antibiotics ineffective, even against strains that do not carry resistance-impairing mutations. This review discusses bacterial iron homeostasis and the strategies being developed to target this bacterial vulnerability, with emphasis on a recently proposed approach which aims at targeting the iron storage protein bacterioferritin (Bfr) and its physiological partner, the ferredoxin Bfd. Bfr regulates cytosolic iron concentrations by oxidizing Fe2+ and storing Fe3+ in its internal cavity, and by forming a complex with Bfd to reduce Fe3+ in the internal cavity and release Fe2+ to the cytosol. Blocking the Bfr-Bfd complex in P. aeruginosa cells causes an irreversible accumulation of Fe3+ in BfrB and simultaneous cytosolic iron depletion, which leads to impaired biofilm maintenance and biofilm cell death. Recently discovered small molecule inhibitors of the Bfr-Bfd complex, which bind Bfr at the Bfd binding site, inhibit iron mobilization, and elicit biofilm cell death.