CBMS Lecture Series

"Manipulating iron storage and mobilization in the bacterial cell, a new strategy for developing antibiofilm interventions". 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 bacterial strains that do not carry resistance-imparting mutations. A key component of iron metabolism is the storage of Fe(III) in bacterioferritin and its subsequent mobilization as Fe(II) to satisfy metabolic requirements. In P. aeruginosa, the mobilization of Fe(III) from bacterioferritin (Bfr) to the cytosol requires binding of a ferredoxin (Bfd) to reduce the stored Fe(III) and release it as the soluble Fe(II). This presentation will discuss evidence showing that deletion of the bfd gene triggers an irreversible accumulation of Fe(III) in BfrB, concomitant intracellular iron deficiency, metabolic dysregulation, and impaired biofilm development. The treatment of Pseudomonas aeruginosa mature biofilms with recently discovered small molecule inhibitors of the BfrB-Bfd complex kills biofilm-entrenched cells. The conservation of Bfr and Bfd amino acid sequences from P. aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae suggest the inhibitors may also be active against these pathogens, and susceptibility testing experiments with A. baumannii support this idea.