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.
","abstract_html":"<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>","abstract_has_math":false,"creators":["Odum, Schyler"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation","degree_discipline":"Biomedical Sciences","degree_department":null,"school":null,"contributors":["Richard Lee"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-01-01T08:00:00Z","date_published":"2025-01-01T08:00:00Z","updated_at":"2026-07-24T05:00:53Z","subjects":["Chemistry","Neurosciences","Physical Sciences and Mathematics"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://dc.uthsc.edu/dissertations/719","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Richard Lee"]},{"key":"dc:creator","label":"Author","values":["Odum, Schyler"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2026-08-22T07:00:00Z"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Biomedical Sciences"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Chemistry","Neurosciences","Physical Sciences and Mathematics"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://dc.uthsc.edu/dissertations/719"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["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.
"]},{"key":"dc:title","label":"Title","values":["Synthesis and Design of ClpP Activators as Novel Antibiotics"]}]}],"canonical_facts":{"dc:contributor":["Richard Lee"],"dc:creator":["Odum, Schyler"],"dc:date.available":["2026-08-22T07:00:00Z"],"dc:description.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.
"],"dc:identifier":["https://dc.uthsc.edu/dissertations/719"],"dc:subject":["Chemistry","Neurosciences","Physical Sciences and Mathematics"],"dc:title":["Synthesis and Design of ClpP Activators as Novel Antibiotics"],"thesis:degree_discipline":["Biomedical Sciences"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T05:00:53Z"}