Building a Trojan Horse: Siderophore-Drug Conjugates for the Treatment of Infectious Diseases.

Abstract

Antimicrobial resistance is a major global health problem, and novel approaches to solving this crisis are urgently required. The 'Trojan Horse' approach to solving this problem capitalizes on the innate need for iron by pathogens. Siderophores are low-molecular-weight iron chelators secreted extracellularly by pathogens to scavenge iron. Once bound to iron, the iron-siderophore complex returns to the pathogen to deliver its iron treasure. "Smuggling" antimicrobials into the pathogen is accomplished by linking them to siderophores for transport. While simple in concept, it has taken many decades of work to accomplish the difficult hurdle of transporting antimicrobials across the cell membranes of pathogens. This review discusses information learned about siderophore structure, production, and transport, and lessons learned from the successes and failures of siderophore-conjugate drugs evaluated during the development of novel agents using the 'Trojan horse' approach.