UC Irvine

Chapter I is a literature review of cyclodepsipeptide natural products containing 13-membered macrolactone rings. “Depsipeptide” refers to any polypeptide containing an ester linkage, and “cyclodespsipeptide” refers to any depsipeptide containing a macrocycle. Cyclodepsipeptide natural products are commonly non-ribosomally synthesized peptides derived from bacteria. For the purposes of this review, I focus on cyclodepsipeptide natural products containing macrolactone rings. The 13-membered macrolactone ring motif in specific is noteworthy due to its biosynthetic origin, in which the β-hydroxyl of the amino acid at the n-3 position forms a macrocyclic ester with the C-terminus. This review provides context for the studies of teixobactin and teixobactin-like peptides in later chapters of the dissertation. Chapter II describes PEGylated teixobactin analogues. At the time of its discovery, teixobactin showed poor solubility in aqueous conditions. I proposed PEGylation, or polyethyleneglycol (PEG) functionalization, of teixobactin as a way to improve its solubility. The syntheses of teixobactin and PEGylated teixobactin analogues, antibacterial efficacy assays, and solubility assays are described. Unexpectedly, PEGylated teixobactins simultaneously show no improvement in solubility and a decrease in antibiotic efficacy. These results lead directly into Chapter III. Chapter III describes “supramolecular antibiotics,” or teixobactin-like antibiotic peptides designed to assemble in a fashion similar to wild type teixobactin. Following the discovery that supramolecular assembly of teixobactin, while imparting poor solubility, is a necessary component of its mechanism of action, I sought to design de novo antibiotics using our structural understanding of wild type teixobactin. These include “chimeras” of teixobactin and an assembly-prone peptide sequence, as well as “swapmers,” which are teixobactin analogues designed with modified tail stereochemistry in order to promote antiparallel β sheet formation. Design, syntheses, and antibacterial efficacy assays of these peptides are described. Chapter IV describes an alanine scan and additional SAR studies of clovibactin, a related antibiotic peptide to teixobactin. Clovibactin contains the unnatural β-hydroxylated amino acid (2R,3R)-3-hydroxyasparagine at the depsicycle position 5. A successful synthesis of Fmoc-protected (2R,3R)-3-hydroxyasparagine by other members of the group enabled an alanine scan, as well as other SAR analogues, of clovibactin. Design, syntheses, antibacterial efficacy assays, and X-ray crystallography of these peptides are described. Chapter V describes a chemistry education research project designed and conducted with Dr. Renée Link, Professor of Teaching. Beginning in 2020, in-person undergraduate general and organic chemistry laboratory courses at UC Irvine were converted to remote delivery in response to the COVID-19 pandemic. When in-person organic chemistry laboratories resumed in 2021, the incoming cohort of students did not have typical hands-on laboratory experience, as they took the prerequisite general chemistry laboratories online. To alleviate this transition from online to in-person labs, we simultaneously (1) developed new, remedial laboratory curricula for the organic laboratory series and (2) introduced a Learning Assistant program for in-person organic chemistry laboratories for non-chemistry majors for the first time at UC Irvine. The initial cohort of Learning Assistants also lacked in-person laboratory experience, so they were trained while beta testing the remedial laboratory curricula. We use coded survey responses to categorize the benefits perceived by students and Learning Assistants in response to the creation of this new program.