Graduation Year
2004
Document Type
Dissertation
Degree
Ph.D.
Degree Granting Department
Chemistry
Major Professor
Edward Turos, Ph.D.
Committee Member
Greg Baker, Ph.D.
Committee Member
Randy Larsen, Ph.D.
Committee Member
Julie Harmon, Ph.D.
Keywords
Antifungal, Anticancer, Antibiotic, Sulfur, MRSA
Abstract
N-Thiolated β-lactams (1) represent a promising new group of compounds with potent inhibition effects on bacteria, like Bacillus anthracis and methicillin resistant Staphylococcus aureus, and onco-systems, like breast cancer and leukemia. Originally developed as part of a synthetic pathway to bicyclic lactams, N-thiolated β-lactams have been shown in this laboratory to possess intriguing biological activities. The antibacterial activities of this new class of agents rely on novel structural features unlike those of any existing family of β-lactam drugs. The lactams seem to exert their effects intracellularly, requiring passage of the bioactive species through the cellular membrane, rather than acting extracellularly on cell wall components in the manner of penicillin and related antibiotics.
The lipophilic nature of these molecules, which lack the polar side chain functionality of all other microbially-active β-lactams, suggests the compounds do not target the penicillin binding proteins within bacterial membranes but instead pass through these membranes. The biological target of these compounds has been investigated. The most active members of this β-lactam class appear to be those bearing a small branched alkyl chain on the sulfur atom. The effects of stereochemistry, branching and chain length of the sulfur group on bioactivities were studied. This dissertation is divided into six chapters. A review of organosulfur anti-infectives is discussed in Chapter 1. The types of existing antibiotics and their modes of action will be discussed in Chapter 2. The synthesis of these novel agents is discussed in Chapter 3. A structure-activity relationship of these lactam analogues is discussed in Chapter 4. And Chapters 5 and 6 demonstrate a novel mode of action and biological target for these drugs using techniques which include target identification, metabolic effects, and reactivity kinetics.
Scholar Commons Citation
Heldreth, Bart Allan, "N-Thiolated β-Lactams: Chemistry, SAR and Intracellular Target of a Novel Class of Antimicrobial and Anticancer Agents" (2004). USF Tampa Graduate Theses and Dissertations.
https://digitalcommons.usf.edu/etd/1074
