| The major focus throughout the body of this thesis is the use of modern medicinal chemistry techniques including, structure-based design, molecular modeling and determination of binding interactions, as well as parallel synthesis of small-molecule libraries directed towards the discovery of novel small-molecule antimicrobials. Chapter 1 briefly details the concepts used in structure-based drug design and gives an overview of the techniques used in modern medicinal chemistry. It also provides an introduction into the development and use of anti-infective agents since their discovery to present time. Chapter 2 details the study of Pantothenate Kinase, the enzyme responsible for the key regulatory step in the Coenzyme A biosynthetic pathway, as a potential drug target for the development of novel antimicrobial compounds. Several compounds synthesized in this study have demonstrated significant enzyme inhibition. Extensive biological testing has also been performed in this study to determine in vitro and in vivo activity, as well as mechanism of antimicrobial action. Chapter 3 covers a preliminary study into the discovery of inhibitors of Aminoglycoside Modifying Enzymes, which are responsible for much of the resistance encountered by this class of antibiotics in bacteria. Proof-of-concept for this study has been well-established by the overwhelming success of clavulanic acid in deactivating beta-lactamases produced by some penicillin-resistant bacteria. Results from this study have yielded the first non-carbohydrate inhibitor of the aminoglycoside modifying enzyme, ANT (2"). Chapter 4 discusses a study on the enzyme mechanism and binding interactions of the transition state of Dihydropteroate Synthase from Bacillus Anthracis. This enzyme is a well-established drug target in an emerging bioterrorism agent. Insight into the enzyme's mechanism of action and key binding interactions will hopefully aid in the development of new inhibitors as therapeutic agents against this pathogen. Finally, chapter 5 presents a summary of the work detailed in this thesis and personal knowledge gained from performing this research. It also includes personal opinions of the entire process and possible directions for the expansion of each process. |
