Siderophore Trojan Horse Antibiotics

Antibiotic-resistant Enterobacteriaceae, including carbapenem-resistant and extended spectrum β-lactamase producing Klebsiella spp., Escherichia coli, and Enterobacter spp. are considered by the Centers for Disease Control and Prevention (CDC) to be urgent and serious health threats to the United States (US), respectively. Carbapenem-resistant Enterobacteriaceae are resistant to all or nearly all available antibiotics and are now considered untreatable. Extended spectrum β-lactamase producing Enterobacteriaceae are responsible for one in five healthcare-associated Enterobacteriaceae infections in the US, at an annual cost of over $1 billion. The prevalence of infections caused by the Enterobacteriaceae and the increase in antibiotic-resistant strains calls for novel therapies to fight these infections. We are developing novel antibiotics for the Enterobacteriaceae - E. coli, K. pneumoniae, Salmonella spp., and Enterobacter spp using siderophores as Trojan horses. Siderophores are powerful iron chelators synthesized and excreted by microorganisms to sequester and return the iron needed for their growth. Because iron is a limiting factor in bacterial growth in the human body (including on skin and in blood, urine and cerebrospinal fluid), siderophores are long-established as virulence factors for all Enterobacteriaceae.