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

Pseudomonas aeruginosa gene PA4880 encodes a Dps-like protein with a Dps fold, bacterioferritin-type ferroxidase centers, and endonuclease activity

“…Ferritin and ferritin-like molecules are particular to iron storage because these molecules catalyze the oxidation of Fe 2+ and compartmentalize the resultant Fe 3+ in their interior cavity. Consequently, in addition to accumulating iron at concentrations much higher than those enabled by the poor solubility of Fe 3+ near neutral pH, ferritin and ferritin-like molecules minimize the toxic effects expected from unregulated Fe 2+ /Fe 3+ redox cycling ( Bradley et al, 2016 ; Rivera, 2017 ; Rivera, 2023 ). The P. aeruginosa PAO1 genome contains four genes encoding iron storage proteins: ftnA (PA4235) encodes a bacterial ferritin (FtnA) ( Yao et al, 2011 ), bfrB (PA3531) codes for a bacterioferritin (BfrB) ( Weeratunga et al, 2009 ; Weeratunga et al, 2010 ), gene PA0962 codes a Dps ( Rajapaksha et al, 2023 ), and gene PA4880, the subject of this report, is annotated to encode a probable bacterioferritin.…”

“…The significant consequences of blocking the Bfr-Bfd complex on P. aeruginosa fitness motivated the discovery of small molecule inhibitors of the BfrB-Bfd complex ( Punchi Hewage et al, 2019 ). These inhibitors have been shown to kill biofilm-embedded P. aeruginosa ( Soldano et al, 2021 ), therefore suggesting the mobilization of iron stored in Bfr as a viable new target for antibiotic discovery ( Rivera, 2023 ).…”

“…Dps are thought to protect DNA by binding and shielding, and by preventing oxidative stress caused by H 2 O 2 in the presence of iron. Dps are 12-mer assemblies of identical subunits with a nearly spherical shell-like structure (∼9 nm diameter) containing a hollow cavity with (∼5 nm diameter) ( Guerra et al, 2021 ; Rivera, 2023 ). The smaller dimensions relative to the 24-mer ferritin and bacterioferritin molecules is the reason Dps are also known as mini ferritins.…”

“…The smaller dimensions relative to the 24-mer ferritin and bacterioferritin molecules is the reason Dps are also known as mini ferritins. The Dps subunit fold consists of a four helix bundle similar to the subunit fold of ferritin and bacterioferritin but with some unique characteristics ( Rivera, 2023 ): ( i ) The subunits of Dps have an N- or C-terminal tail not present in ferritin or bacterioferritin, ( ii ) the long loop connecting helices B and C in the Dps four helix bundle contains a short α-helix, which is absent in ferritin and bacterioferritin, and ( iii ) Dps harbor two di-iron ferroxidase centers at the interface of each subunit dimer, where the ferroxidase center ligands are contributed by residues from both subunits. These ferroxidase centers are distinct from the ferroxidase centers in ferritin and bacterioferritin, which are buried in the middle of each subunit.…”