Synthesis and Design of ClpP Activators as Novel Antibiotics

<p>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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biomedical Sciences

Year dc:date.available

2025

Author dc:creator

• Odum, Schyler

Contributors dc:contributor

• Richard Lee

• Chemistry
• Neurosciences
• Physical Sciences and Mathematics

Repository record dc:identifier

https://dc.uthsc.edu/dissertations/719

OAI identifier oai:identifier

oai:dc.uthsc.edu:dissertations-1719