Targeting *Staphylococcus aureus* siderophore pathways offers novel antimicrobial strategies against MRSA

Staphylococcus aureus, including MRSA, poses a significant global health threat due to its increasing antibiotic resistance. A critical factor for bacterial survival and virulence, especially under iron-restricted conditions within the host, is efficient iron acquisition. Current antibiotic strategies often fail against resistant strains, necessitating novel approaches. This review explores bacterial siderophores, non-ribosomal peptides that chelate iron, as a promising mechanism to target, offering a new avenue for antimicrobial development.

This narrative review systematically examined preclinical and clinical studies, reviews, and meta-analyses published between 2019 and 2025. Researchers included 55 references based on relevance, currency, and methodological quality. The review focused on the mechanisms of Staphylococcus aureus iron acquisition via polycarboxylate siderophores, specifically staphyloferrin A and B, and their associated biosynthetic pathways and transport systems. It also evaluated recent studies on small-molecule inhibitors and siderophore-antibiotic conjugates.

The review elucidated that Staphylococcus aureus relies on polycarboxylate siderophores, staphyloferrin A and B, for survival in iron-limited environments. Their biosynthesis proceeds via non-ribosomal peptide synthetase (NRPS)-independent routes, governed by the sfna and sbn gene clusters. Key enzymes involved in staphyloferrin B formation, including SbnA, SbnC, SbnE, SbnG, and SbnH, were identified as promising drug targets due to their critical catalytic functions. Recent studies have demonstrated the efficacy of small-molecule inhibitors, such as citrate analogs and baulamycins, which target these enzymes. These inhibitors have shown potential to reduce bacterial growth and virulence. Furthermore, the 'Trojan horse' approach, utilizing siderophore-antibiotic conjugates, including newly designed Staphylococcus-specific analogs based on staphyloferrin A, has emerged as a compelling strategy. This method leverages the bacterial iron uptake machinery to deliver antibiotics directly into the cell, potentially overcoming resistance mechanisms.

Targeting siderophore pathways, particularly the biosynthetic enzymes, offers an effective route for combating MRSA and other resistant bacteria by disrupting their essential iron acquisition.