Alternative Drug Discovery Platforms for the Identification of Anti-Infective Agents

Chapter 1 of this dissertation explores the application of a high throughput fragment-based screening approach known as kinetic target-guided synthesis (KTGS) for the identification of pathogenic free-living amoeba (pFLA) glucokinase inhibitors. This alternative discovery approach utilizes selected reaction monitoring (SRM) liquid chromatography tandem mass spectrometry (LC-MS/MS) for hit detection, enabling the incubation of 190 fragment combinations per screening well. 1,710 N-acylsulfonamides were screened against Naegleria fowleri glucokinase (NfGlck), leading to the identification of 12 inhibitors against 3 pFLA glucokinase – Balamuthia mandrillaris Glck (BmGlck), and Acanthamoeba castellanii Glck (AcGlck).Chapter 2 of this dissertation describes the design and synthesis of CGS 15943 analogs as a follow-up to a high throughput screen that identified several anti-plasmid inhibitors. The development of antibacterial adjuvants is an emerging alternative strategy to combat the rise of multi-drug resistant (MDR) bacteria. CGS 15943 was identified as a highly selective antiplasmid compound, capable of completely eliminating plasmids bearing carbapenemase resistance genes in tolc Escherichia coli. This study explores our attempts to develop CGS 15943 analogs that may retain potency in wildtype K12 E. coli.Chapter 3 of this dissertation describes the design and synthesis of pyrazole-thiazole core-antibacterial adjuvants. Following a structure activity relationship (SAR) investigation, 20 compounds were developed that demonstrated the ability to potentiate meropenem, a broad-spectrum β-lactam inhibitor, against a MDR strain of Klebsiella pneumoniae.