Design, Synthesis, and Evaluation of Small Molecules in the Discovery of Novel Antimicrobial Agents

<p>The increasing prevalence of antibiotic-resistant bacteria, including Mycobacterium tuberculosis, Streptococcus pneumoniae, Staphylococcus aureus, and Enterococcus faecalis, pushes us to discover new antibacterial agents to maintain adequate patient coverage. This body of work highlights the use of medicinal chemistry methodologies that encompass cross-disciplinary fields of study. Chapter 1 gives an introduction to the antibacterial drug targets, resistance, and how scientists are working to overcome obstacles encountered with drug-resistant bacteria. It also details modern medicinal chemistry applications in antimicrobial drug discovery. Chapter 2 details the use of a structure-guided library approach to drug design, in which large virtual libraries against the target are generated and filtered, based on pharmacophoric and structural constraints, to produce smaller and more structurally complex libraries prioritized for synthesis. In this work, bi-aryl sulfonamide libraries using contemporary medicinal chemistry techniques were synthesized as potential inhibitors of Mycobacterium tuberculosis cell wall biosynthesis via the rhamnose pathway. Chapter 3 describes the discovery of novel inhibitors of the PlsX/PlsY pathway to phosphatidic acid, a key intermediate in the biosynthesis of phospholipids in Gram-positive bacteria. Substrate mimics, incorporating various bioisosteric replacement head groups, were discovered demonstrating good enzyme inhibition and good antimicrobial activity against clinically relevant bacteria. Finally, Chapter 4 provides an overall discussion of the work detailed in this dissertation and future directions that will continue the advancement of these projects. </p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Medicinal Chemistry

Year dc:date.available

2008

Author dc:creator

• Grimes, Kimberly D.

Contributors dc:contributor

• Richard E. Lee, Ph.D.

• Combinatorial chemistry; parallel synthesis; tuberculosis; Gram-positive bacteria; sulfonamides; acylphosphates
• Medical Sciences
• Medicine and Health Sciences
• Other Medical Sciences
• Pharmaceutics and Drug Design
• Pharmacy and Pharmaceutical Sciences

Repository record dc:identifier

https://dc.uthsc.edu/dissertations/114

OAI identifier oai:identifier

oai:dc.uthsc.edu:dissertations-1104