Synthesis and Biological Testing of Glycosylated Fluoroquinolone Antibiotics

The last 70 years have been dubbed the "Antibiotic Era." During that time, the development of bacterial resistance has been observed for every class of antibiotics that have been introduced in the clinic. There is, and will likely continue to be, an urgent need for the development of novel ways of combating bacteria and of dealing with the problem of antibiotic resistance.;The Phosphoenolpyruvate Transferase System (PTS) is a sugar transport system found uniquely in prokaryotes that uses the energy from phosphenolpyruvate (PEP) to phosphorylate the 6'-primary hydroxyl of a hexose sugar while concomitantly transporting the sugar into the bacterial cytosol. The idea that the PTS might be used as a means of antibacterial drug delivery has been proposed since the late 1970s, but validation of this concept still remains an open field of research.;This thesis describes our efforts to develop glycosylated fluoroquinolones that might be transported via the bacterial PTS. To this end, we synthesized different glycosylated fluoroquinolones and also developed a synthetic route to access their corresponding 6'-primary phosphates. By utilizing the reagent NBD-Fluoride, we were able to significantly improve the synthesis of 2-NBDG, a fluorescent analog of glucosamine that is known to be transported by the bacterial PTS. However, due to difficulties with our biological uptake assay, we were unable to determine whether our glycosylated fluoroquinolones were substrates for the bacterial PTS.