Date of Award

12-10-2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Binghe Wang

Second Advisor

Gregory Poon

Third Advisor

Suri Iyer

Abstract

Chemical probes are important tools in examining biological mechanisms and potential therapeutics. Along the direction of studying sulfur signaling, perthiol species (RSnH, n≥2) and hydrogen polysulfides (H2Sn, n≥2) play essential roles in various physiological and pathological pathways and have promising therapeutic potentials such as vasodilation, anti-inflammation, and anti-oxidation effect. They can directly influence protein activity by post-translational modification. One of the major bottlenecks in researching the roles of perthiol species and hydrogen persulfide is the lack of proper prodrugs as both research tools and therapeutic reagents. Herein, we have developed a series of enzyme-sensitive prodrugs of perthiol species and hydrogen polysulfides with a controllable release mechanism and kinetics. The utility of these prodrugs has been validated in various biological models.

Life-threatening infections caused by multi-drug resistant (MDR) bacteria pose a great threat to public health. The emergence of MDR bacteria at an increasing rate coincides with a decrease in new antibiotics development. Therefore, there is an urgent need for the discovery of new antimicrobials to counter this looming health problem. Along this line, we have developed compounds that sensitize Gram-negative strains towards a wide range of existing antibiotics, including those that are otherwise narrow-spectrum and not effective against Gram-negative bacteria. These compounds work by disrupting the outer membrane of Gram-negative bacteria. Very importantly, such sensitizers exhibited a much lower propensity to induce resistance in bacteria than commonly used antibiotics.

Available for download on Saturday, November 21, 2020

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