Synthesis and Modification of Phenolate-based Artificial Siderophores

Abstract

The rise of microorganisms resistant to standard medications poses a significant threat to public health in the 21st century. As once-treatable infections become increasingly life-threatening, there is an urgent need for alternative therapeutic strategies that can keep pace with rapidly evolving pathogens. One promising approach is the development of siderophore-antibiotic conjugates, which exploit bacterial iron acquisition pathways to deliver antibiotics directly into bacterial cells—a mechanism commonly referred to as the ‘Trojan Horse’ strategy. Recent advances in this area have resulted in the development of synthetic siderophores with notable activity, including cefiderocol, which has been approved for clinical use. Human serum was recently found to be an effective bacterial growth medium for high- throughput discovery of synthetic siderophores. Screening of compound libraries using this approach led to the identification of our initial hit, which emerged as the most potent growth enhancer among 29,208 compounds tested. This project focuses on the design and synthesis of novel siderophores and siderophore-antibiotic conjugate analogues inspired by the initial hit, aiming to explore their structure–activity relationship and understand how siderophore modifications influence iron binding and bacterial uptake. The iron-binding motif within this scaffold remains relatively unexplored, adding a novel and compelling aspect to the project. The contribution of different functional groups to iron acquisition were investigated through the synthesis of various analogues, and the first siderophore–antibiotic conjugate incorporating ampicillin, a broad-spectrum antibiotic, was successfully synthesized.