| The discovery of antibiotics had an enormous impact on medicine because it revolutionized medical procedures and prolonged the life expectancy of patients. The unrestricted, yet indispensable, use of antibiotics in clinics has led to the accumulation of infections associated with drug resistant strains of bacteria. The majority of the antibiotics that are commonly utilized were discovered during the 'golden age' --- the 1940s to 1960s --- of antibacterial discovery. Unfortunately, no new classes of antibiotics have been discovered in 29 years. The prevalence of antibiotic resistant bacteria and the lack of discovery have produced a difficult situation that necessitates global attention and collaborative action. In this thesis, we describe our contribution to filling the antibacterial discovery void. We illustrate several discovery strategies used in antibiotic research and explain experimental characterization challenges in the context of identifying inhibitors of the cytoskeletal protein, FtsZ. We describe the mechanism of action and new potent analogs of a new class of narrow spectrum DNA gyrase inhibitors. We characterize a new class of broad-spectrum membrane-targeting small molecules with a unique phenotype using a structure-activity relationship study and cell imaging studies. Finally, we identified another class of membrane-targeting small molecules, which demonstrate potential as antibiotic adjuvants against clinically relevant gram-negative and gram-positive bacteria. These projects have provided promising small molecules with antibacterial activity and therapeutic potential as antibiotics. |
