Exploiting siderophores and related proteins for antimicrobial strategies in Staphylococcus aureus: A review

Iron acquisition is crucial for bacterial growth and virulence. This review examines how Staphylococcus aureus utilizes its polycarboxylate siderophores, staphyloferrin A and B, to survive under iron-restricted conditions. Their non-ribosomal peptide synthetase (NRPS)-independent biosynthetic routes and Fe³⁺ transport mechanisms are described, with a particular focus on the sfna and sbn gene clusters. The enzymes SbnA, SbnC, SbnE, SbnG, and SbnH involved in staphyloferrin B formation are discussed in terms of their structures, catalytic functions, and potential as drug targets. Recent studies on small-molecule inhibitors such as citrate analogs and baulamycins have highlighted these enzymes as promising therapeutic targets for intervention. In addition, the review considers the "Trojan horse" approach using siderophore-antibiotic conjugates, including newly designed Staphylococcus-specific analogs based on staphyloferrin A. Together, these insights suggest that targeting siderophore pathways may offer an effective route for combating MRSA and other resistant bacteria, while emphasizing the need for structural data on staphyloferrin A biosynthetic enzymes.