Abstract:

In 2015, teixobactin was reported as a promising new antibiotic candidate. Teixobactin is a non-ribosomal depsipeptide with potent antibiotic activity against Gram-positive bacteria, including drug-resistant strains such as MRSA and VRE. Unfortunately, teixobactin aggregates to form gels in the physiological conditions needed for intravenous administration. The limited solubility and propensity of teixobactin to form gels has the potential to jeopardize its promise as a clinically useful intravenous antibiotic against drug-resistant Gram-positive pathogens by limiting dosing to low concentrations that do not form gels or aggregates.

In this thesis defense, I will be discussing the design and development of O-acyl isopeptide prodrugs of teixobactin and teixobactin analogues, which we have termed isobactins. First, I will describe the first synthesis of numerous isobactin prodrug analogues that address the problem of gel formation while retaining antibiotic activity. Next, I will discuss the investigation of additional isobactin prodrug analogues through a small SAR study using commercially available amino acids. Lastly, I will summarize my efforts towards the synthesis of natural teixobactin and isobactins A, B, and C.