Use of modern structure-based drug design techniques in the discovery and development of novel antimicrobial candidates

The common theme throughout this dissertation is the use of structure-based drug design in the discovery and advancement of novel antibacterial compounds. Chapter 1 introduces the topic of structure-based design and outlines some of the basic concepts in the two major methodologies of the dissertation, virtual screening and X-ray crystallography. Chapter 2 details a virtual screening project, targeting a novel therapeutic target in Mycobacterium tuberculosis . Novel inhibitors of an essential enzymatic pathway in M. tuberculosis with activity against whole cells have been discovered in this study. The work done in this chapter demonstrates modern structure-based design methodologies and how they are currently being applied in drug design. Chapter 3 contains a study done using X-ray crystallography to study the macromolecular structure of a well-established drug target in the bioterrorism agent Bacillus anthracis. The studies in this chapter have yielded important new information into the enzymatic mechanism, as well as insight into future inhibitor design. Finally, Chapter 4 presents a summary of the lessons learned from conducting these experiments, as well as personal opinion on the entire process as a whole.