The leading infectious disease threat in the world is tuberculosis (TB) caused by the bacterium Mycobacterium tuberculosis (M. tuberculosis). Although TB is preventable and treatable, the emergence of multidrug-resistant (MDR) strains highlights the need for the development of new drugs with novel modes of action. A proposed target for fighting TB is the non-mevalonate pathway (MEP). MEP is absent in humans whereas, in M. tuberculosis and Escherichia coli (E. coli), it is responsible for the synthesis of isoprenoids, essential compounds for their life cycle. Fosmidomycin is a natural antibiotic that inhibits the MEP pathway through inhibition of the enzyme 1-deoxylulose-5-phosphate reductoisomerase (DXR). Even though fosmidomycin shows potent in vitro activity against DXR, its polar character renders it membrane impermeable. Nonetheless, in pathogens such as E. coli, the active uptake of fosmidomycin is mediated by the glycerol- 3-phosphate transporter (GlpT). Fosmidomycin effectively inhibits mycobacterial DXR, but it is not active against mycobacteria due to their highly hydrophobic cell wall and the absence of a corresponding GlpT transporter. The present work describes the development of fosmidomycin analogs to improve both passive membrane diffusion and dependency of fosmidomycin from GlpT. Through experimentation, the negatively charged phosphonate group in fosmidomycin was replaced with a fluorophosphonate moiety, a less polar chemically reactive isosteres. This modification leads to the development of covalent analogs of fosmidomycin introducing a novel strategy of inhibition for DXR. In addition, the current work describes the development of the γ-borono phosphonate compounds that are rationally designed analog of fosmidomycin. Despite their structural similarity, the γ- borono phosphonates exhibit an antimicrobial activity against E. coli with a unique mechanism of action, suggesting they may serve as lead compound to develop a novel antimicrobial class. Moreover, structure activity relationship studies indicate the importance of the boronic acid functionality, the phosphonate group, and the three-carbon backbone for antimicrobial activity. Cytotoxicity analysis also shows that the γ-borono phosphonates are not toxic to the mammalian cells. However, the mechanism of action is still unclear although we suggest that the γ-borono phosphonate class does not act as an anti-biofilm agent.
|Advisor:||Tomsho, John W.|
|Commitee:||Wang, Zhihong, Adejare, Adeboye , Fasella, Elisabetta, Converso, Antonella|
|School:||University of the Sciences in Philadelphia|
|School Location:||United States -- Pennsylvania|
|Source:||DAI-B 82/7(E), Dissertation Abstracts International|
|Subjects:||Organic chemistry, Pharmacology|
|Keywords:||Tuberculosis, Glycerol- 3-phosphate transporter, 1-deoxylulose-5-phosphate reductoisomerase|
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