Doctor of Philosophy (PhD)
The research presented in this dissertation explores a novel pragmatic therapeutic approach for control, prevention, and treatment of infectious disease using Active-Pharmaceutical Ingredient-based Ionic Liquids (API-ILs) and Groups of Uniform Materials Based on Organic Salts (GUMBOS). Accordingly, several antiseptic- and antibiotic-based API-ILs and GUMBOS were synthesized and characterized using a combination of analytical and microbiological techniques. Overall, this research presents an advanced alternative to combination antibiotic therapy by using a novel group of ionic antimicrobial materials that have controlled pharmacokinetics, improved bioavailabilities, reduced toxicities, multi-modal properties, and potent antimicrobial spectrum of activity as a viable alternative to combating bacterial infections. The first part of this research provides the physical characterization and subsequent in vitro antimicrobial activity of ampicillin-based ILs consisting of several different quaternary ammonium compounds (QACs) on Escherichia coli O157:H7, Klebsiella pneumoniae, Staphylococcus aureus, and Listeria monocytogenes. The synthesized API-ILs were validated with proton nuclear magnetic resonance spectroscopy (NMR) and elemental analysis. Melting points, critical micelle concentrations, and solubility were among the other physical properties investigated. Improved antibacterial activity was evaluated using Loewe’s Additivity Mathematical Model and interaction indices were established and compared to mixtures of precursor QACs and ampicillin. The second part of the dissertation research focuses on the synthesis and antibacterial activity of GUMBOS created from an antiseptic and several â-lactam antibiotics. Using anion metathesis, four â-lactam antibiotic-based chlorhexidine GUMBOS were synthesized prior to validation using proton and carbon NMR, mass spectrometry, elemental analysis, and absorbance spectroscopy. Several orders of improvement in in vitro antibacterial activities were obtained on isolates of Escherichia coli O157:H7, Salmonella typhi, Acinetobacter baumanii, Enterobacter clocae, Enterobacter aerogenes, Klebsiella pneumoniae, Pseudomonas aeruginosa, Serratia marscescens, Staphylococcus aureus, Streptococcus mutans Streptococcus facaelis, Micrococcus luteus, Bacillus cereus, and Methicillin-resistant Staphylococcus aureus. Interaction indices show the GUMBOS to be synergetic ion-pairs despite additivity and antagonism observed by the mixtures of antiseptic and antibiotic precursor ions. Furthermore, the mechanisms of action studies for these materials were defined with emphasis on membrane permeability and membrane potential. Finally, acute cytotoxicity against fibroblast, endothelium, and cervical cellular lines in addition to an assessment of intestinal permeability and bioavailability were completed.
Document Availability at the Time of Submission
Release the entire work immediately for access worldwide.
Cole, Marsha Rae, "Chemical and biological evaluation of antibiotic-based ionic liquids and GUMBOS against pathogenic bacteria" (2012). LSU Doctoral Dissertations. 487.
Warner, Isiah M.