Siderophore–drug complexes: potential medicinal applications of the ‘Trojan horse’ strategy

•A Trojan horse strategy based on siderophore–drug complexes holds great promise in several medical applications. •Siderophore-based therapeutics have potential in the treatment in iron overload. The ability of bacteria to develop resistance to antimicrobial agents poses problems in the treatment of numerous bacterial infections. One method to circumvent permeability-mediated drug resistance involves the employment of the ‘Trojan horse’ strategy. The Trojan horse concept involves the use of bacterial iron uptake systems to enter and kill bacteria. The siderophore–drug complex is recognized by specific siderophore receptors and is then actively transported across the outer membrane. The recently identified benefits of this strategy have led to the synthesis of a series of siderophore-based antibiotics. Several studies have shown that siderophore–drug conjugates make it possible to design antibiotics with improved cell transport and reduce the frequency of resistance mutants. Growing interest in siderophore–drug conjugates for the treatment of human diseases including iron overload, cancer, and malaria has driven the search for new siderophore–drug complexes. This strategy may have special importance for the development of iron oxide nanoparticle-based therapeutics. The ability of bacteria to develop resistance to antimicrobial agents poses problems in the treatment of numerous bacterial infections. One method to circumvent permeability-mediated drug resistance involves the employment of the ‘Trojan horse’ strategy. The Trojan horse concept involves the use of bacterial iron uptake systems to enter and kill bacteria. The siderophore–drug complex is recognized by specific siderophore receptors and is then actively transported across the outer membrane. The recently identified benefits of this strategy have led to the synthesis of a series of siderophore-based antibiotics. Several studies have shown that siderophore–drug conjugates make it possible to design antibiotics with improved cell transport and reduce the frequency of resistance mutants. Growing interest in siderophore–drug conjugates for the treatment of human diseases including iron overload, cancer, and malaria has driven the search for new siderophore–drug complexes. This strategy may have special importance for the development of iron oxide nanoparticle-based therapeutics. cyclophosphamide, etoposide, carboplatin, and thiotepa. cyclophosphamide–adriamycin–vincristine–prednisone. outer-membrane receptor from E. coli for ferric enterobactin. outer-membrane ferric dicitrate receptor of E. coli. outer-membrane receptor from E. coli for ferric ferrichrome. periplasmic binding proteins from E. coli. outer-membrane receptor from P. aeruginosa for ferric pyochelin. outer-membrane receptor from P. aeruginosa for ferric pyoverdin. cytoplasmic transmembrane complex, consisting of the proteins TonB, ExbB, and ExbD, that spans the periplasm. TonB, ExbB, and ExbD are cytoplasmic membrane proteins of the energy-transducing protein complex.