Date of Award
2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Program
Biomedical Sciences
Track
Molecular and Systems Pharmacology
Research Advisor
Richard Lee
Committee
Alejandro Dopico; Daniel Blair; Kirk Hevener; Tommaso Cupido
Abstract
Purpose. Design and synthesize novel compounds to treat Staphylococcus aureus infections by targeting the dysregulation of the Casein Protease P, ClpP. Methods. Utilize established chemical methods to synthesize ureadepsipeptides, small-molecule ClpP activators, and ureadepsipeptide hybrids. Assess their effectiveness by using minimum inhibitory concentration assays and in vitro biochemical assays for ClpP activation. Explore their potential as antibiotics through mitochondrial toxicity tests, glucose/galactose assays, and biophysical measurements related to metabolism and clearance, including thermal shift and surface plasmon resonance assays. Results. Synthesized and tested 33 novel compounds, comprising a total of 80 synthetic steps. Conclusion. The three-part conclusion from the dissertation is that: Heterocycles and bulky side chains are not well tolerated in the ureadepsipeptide structure at the phenylurea position, and a LogD of approximately 2 serves as a good marker for whole-cell activity. Small-molecule ClpP activators can achieve MIC activity but require further optimization for specificity against S. aureus. Biasing the pucker state of the southern proline on the UDEP macrocycle increases MIC activity, but attaching siderophore sidechains to the southern proline via a short linker does not confer broad-spectrum activity to UDEPs.
ORCID
0009-0007-0397-0896
DOI
10.21007/etd.cghs.2025.0699
Recommended Citation
Odum, Schyler (0009-0007-0397-0896), "Synthesis and Design of ClpP Activators as Novel Antibiotics" (2025). Theses and Dissertations (ETD). Paper 719. http://dx.doi.org/10.21007/etd.cghs.2025.0699.
https://dc.uthsc.edu/dissertations/719