The Role of Bacterial Siderophores in Infection Therapy: From Anti-Infective Mechanisms to Therapeutic Advances

Siderophores are low-molecular-weight iron chelators that mediate microbial iron acquisition and critically shape host-pathogen interactions. This review highlights the structural diversity, regulatory networks, and virulence functions of bacterial siderophores, including their roles in overcoming host nutritional immunity, modulating immune responses, promoting biofilms, and coordinating metal homeostasis. We further discuss therapeutic strategies that exploit siderophore pathways, from "Trojan horse" siderophore-antibiotic conjugates such as cefiderocol to emerging non-antibiotic conjugates incorporating metal complexes, peptides, nucleic acids, vaccines, and nanomaterials. Beyond antibacterial applications, siderophores show promise in antifungal and antiparasitic therapies and as infection-specific imaging probes. Despite these advances, translational challenges-including adaptive resistance, pharmacokinetic instability, and competition with endogenous siderophores-limit clinical progression. Innovative approaches such as engineered siderophore scaffolds, multifunctional delivery platforms, and nanotechnology-enabled systems may help overcome these barriers. Overall, this review underscores the central role of siderophores in microbial pathogenesis and their growing potential as versatile platforms for next-generation anti-infective and diagnostic development.