Exploiting Bacterial Iron Acquisition: From New Antibiotics to Pathogen Detection Devices

Siderophores are an important class of natural products that have received wide attention for many years due to their unique properties as microbial iron chelators and potential use in drug delivery, imaging, and most recently in diagnostics. Significant advances have been made in the past decade, but additional studies and applications show promise for extended utility.

In chapter 2, design and practical synthesis of a triscatecholate siderophore as an artificial enterobactin mimic for delivery of aminopenicillin are described. The aminopenicillin conjugates exhibited sgnificantly enhanced in vitro antibacterial activities against Gram-negative species compared to the parent drugs, especially against Pseudomonas aeruginosa. Using the triscatecolate siderophore for delivery of other antibacterial agents that have different cellular targets and modes of action is also presented.

Further attention in development of controlled drug release processes from siderophore-drug conjugates will expand the drug profiles and types of intracellular targets that can be considered. Design, syntheses and antibacterial activity of siderophore-drug conjugates with potential drug release linkers triggered by different microbial actions are described in chapter 3 and 4. Conjugates with a reduction triggered linker displayed better antibacterial activity compared to the respective non-releasable conjugate, indicating that the expected drug release process occurs. Broad biological evaluations of synthetic intermediates were also performed and led to the discovery of several potent N-acylated ciprofloxacin derevatives which may act through a novel dual-action mechanism.

Besides drug delivery, siderophore metal complexes and conjugates have considerable potential for use as new pathogen detection devices. Development of such a device on a microfluidic chip using both natural and artificial siderohpore was explored and presented in chapter 5. Once completed, this could provide a new generation of strain-selective pathogen detection device.

In addition, palladium-catalyzed cyclopropanations of various nitroso Diels-Alder (NDA) cycloadducts are described in chapter 6. The methodology reported led to quick access of a conformationally restricted carbocyclic nucleoside which represents a family of biologically useful molecules.