posted on 2024-03-14, 13:05authored byChuchu Guo, Elizabeth M. Nolan
ConspectusSiderophores are secondary metabolites
utilized by bacteria to
acquire iron (Fe), an essential transition metal nutrient. Fe levels
in the host environment are tightly regulated and can be further restricted
to starve invading bacterial pathogens in a host-defense process known
as nutritional immunity. To survive and colonize the Fe-limited host
environment, bacteria produce siderophores and express cognate siderophore
transport machinery. These active transport pathways present an opportunity
for selective and efficient drug delivery into bacterial cells, motivating
decades of research on synthetic siderophore–antibiotic conjugates
(SACs) as a Trojan-horse strategy for the development of targeted
antibiotics.Enterobactin (Ent) is a triscatecholate siderophore
produced and
utilized by many Gram-negative bacteria, including all Escherichia
coli and Salmonella species. Within these
species, pathogenic strains cause a variety of human diseases including
urinary tract infections, gastroenteritis, and sepsis. Infections
caused by these Gram-negative pathogens can be difficult to treat
because of the impermeability of the outer membrane (OM). This impermeability
can be overcome by utilizing siderophores as drug delivery vectors
for targeting Gram-negative pathogens. Ent is a promising delivery
vector because it undergoes active transport across the OM mediated
by the Ent uptake machinery after scavenging Fe(III) from the extracellular
environment. Despite the well-elucidated chemistry and biology of
Ent, its use for SAC development was hampered by the lack of an appropriate
functional group for cargo attachment. Our laboratory addressed this
need by designing and synthesizing monofunctionalized Ent scaffolds.
Over the past decade, we have used these scaffolds to explore Ent-based
SACs with a variety of drug warheads, including β-lactam and
fluoroquinolone antibiotics, and Pt(IV) prodrugs. Investigations of
the antibacterial activities of these conjugates and their cellular
fates have informed our design principles and revealed approaches
to achieving enhanced antibacterial potency and pathogen-targeted
activity. Collectively, our studies of Ent–drug conjugates
have provided discoveries, understanding, and invaluable insights
for future design and evaluation of SACs.In this Account, we
present the story of our work on Ent–drug
conjugates that began about ten years ago with the development of
monofunctionalized Ent scaffolds and the design and synthesis of various
conjugates based on these scaffolds. We describe the antibacterial
activity profiles and uptake pathways of Ent–drug conjugates
harboring traditional antibiotics and repurposed platinum anticancer
agents as well as studies that address cellular targets and fates.
Finally, we discuss other applications of monofunctionalized Ent scaffolds,
including a siderophore-based immunization strategy. We intend for
this Account to inspire further investigations into the fundamental
understanding and translational applications of siderophores and siderophore–drug
conjugates.