Siderophores: Chemical tools for precise antibiotic delivery

The success of precision medicine coupled with the disappointing impact of broad-spectrum antibiotic use on microbiome stability and bacterial resistance, has triggered a shift in antibiotic design strategies toward precision antibiotics. This also includes the implementation of novel vectorization approaches directed to improve the internalization of antibacterial agents into deadly gram-negative pathogens through precise and well-defined mechanisms. The conjugation of antibiotics to siderophores (iron scavengers), which are compounds that are able to afford stable iron-complexes that facilitate the internalization into the cell by using bacterial iron uptake pathways as gateways, is a strategy that has begun to show excellent results with the commercialization of the first antibiotic based on this principle, cefiderocol. This digests review provides an overview of the molecular basis for this antibiotic-siderophore conjugation approach, along with recent successful examples and highlights future challenges facing this booming research area.