Structural, functional, and evolutionary perspectives of bacterial iron repertoire: bacterioferritin and bacterioferritin-associated ferredoxin as emerging targets against antibiotic resistance.

Bacterioferritin (Bfr), traditionally recognized as a bacterial iron storage protein, functions synergistically with its partner, bacterioferritin-associated ferredoxin (Bfd), which mediates iron release. Recent research has highlighted these proteins for their remarkable structural characteristics and their indispensable role in maintaining cellular iron homeostasis. Their evolutionary conservation across diverse bacterial lineages indicates broader physiological functions, such as supporting cellular maintenance, enhancing virulence, and facilitating stress adaptation. Bfr forms a 24-meric macromolecular assembly that stores iron in its ferric state, thereby protecting the cell from iron-induced oxidative stress. In contrast, twelve Bfd molecules associated with Bfr facilitate iron mobilization by electron donation, reducing ferric to ferrous iron, thus enabling its release from the Bfr cage. This regulated system of iron sequestration and mobilisation is widespread among bacteria, but is notably absent in Lactobacilli. This review explores the structural dynamics and evolutionary conservation of Bfr and Bfd, emphasising their molecular interactions. Considering the escalating threat of antimicrobial resistance (AMR), disrupting this essential protein–protein interface presents a promising therapeutic strategy. By providing detailed insights into their structure, function, and evolutionary relevance, this review identifies the Bfr-Bfd complex as a potential target for developing novel antimicrobial interventions.