Theses and Dissertations at Montana State University (MSU)
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Item Design, synthesis, and evaluation of novel antimicrobials for the eradication of biofilms(Montana State University - Bozeman, College of Letters & Science, 2020) Walsh, Danica Jade; Chairperson, Graduate Committee: Thomas S. Livinghouse; Thomas Livinghouse was a co-author and corresponding author and Darla M. Goeres, Madelyn Mettler, and Philip S. Stewart were co-authors of the article, 'Antimicrobial activity of naturally occurring phenols and derivatives against biofilm and planktonic bacteria' in the journal 'Frontiers in chemistry' which is contained within this dissertation.; Thomas Livinghouse was a co-author and corresponding author and Greg M. Durling, Yenny Chase-Bayless, Adrienne D. Arnold and Philip S. Stewart were co-authors of the article, 'Sulfenate esters of simple phenols exhibit enhanced activity against biofilms' submitted to the journal 'ACS Omega' which is contained within this dissertation.; Thomas Livinghouse was a co-author and corresponding author and Greg Durling, Adrienne Arnold, Whitney Braiser, Luke Berry, Darla M. Goeres and Philip S. Stewart were co-authors of the article, 'Enhanced antimicrobial activity of prodrug phenols against biofilms and planktonic bacteria' which is contained within this dissertation.The majority of microorganisms live in association with surfaces as biofilms. Biofilm communities are encased in a robust, extracellular matrix that reduces their susceptibility to antimicrobial agents. This poses a health concern due to the potential for pathogenic bacteria to cause serious infections. For example, hospital-acquired infections are among the top ten leading causes of death in the U.S. and are responsible for nearly 23,000 deaths per year. The goal of my research is to develop efficient antimicrobial agents capable of eradicating biofilms. In this project, I have focused on three different derivatizations of small, phenolic compounds in effort to increase efficacy towards biofilms. An initial study compared the potency of small, naturally occurring phenols and their corresponding allyl, propyl, and methallyl derivatives against bacteria. This study showed that in parent and derivative pairs potency increased towards free floating cells but decreased towards biofilms. This illustrated the importance of evaluating antimicrobial efficacy toward biofilms when the bacteria they intend to treat has the propensity to form biofilms. This was in contrast to a second studyishowing that trichloromethylsulfenate ester derivatives generally increased potency towards both biofilms and planktonic cells. In a third study, we found that iminodiacetoxy-methylester (AM) appendages increase potency towards planktonic cells and biofilms. AM appendages are ester groups that are employed as part of a prodrug design. Prodrugs are biologically inactive compounds until metabolized. Ester groups are commonly used in prodrug intracellular dyes, where, once inside the cell, ester groups are cleaved enzymatically, resulting in a negatively charged dye that is retained in the cell. Similarly, after the cleavage event, the AM antimicrobial compound will concentrate within the cell. This design serves two functions to increase potency: increasing permeability towards the biofilm matrix and achieving cellular retention. We have shown that the efficacy of antimicrobial agents towards biofilms can be increased through this strategic design. This class of prodrugs presents a wide array of potential applications, from controlling hospital-acquired infections to incorporation into household cleaning products and addresses the need for novel treatments of pathogenic bacteria.Item Investigations into the activity of synthetic & natural products against methicillin-resistant Staphylococcus aureus(Montana State University - Bozeman, College of Letters & Science, 2016) Weaver, Alan James, Jr.; Chairperson, Graduate Committee: Martin Teintze; Joyce B. Shepard, Royce A. Wilkinson, Robert L. Watkins, Sarah K. Walton, Amanda R. Radke, Thomas J. Wright, Milat B. Awel, Catherine Cooper, Elizabeth Erikson, Mohamed E. Labib, Jovanka M. Voyich and Martin Teintze were co-authors of the article, 'Antibacterial activity of Tham trisphenylguanide against methicillin-resistant Staphylococcus aureus' in the journal 'PLoS ONE' which is contained within this thesis.; Abigail Van Vuren, Rakesh, Richard E. Lee, Valerie Copié and Martin Teintze were co-authors of the article, 'Exposure of methicillin-resistant Staphylococcus aureus to low levels of the antibacterial Tham-3 phi G generates a small colony drug-resistant phenotype' submitted to the journal 'PLoS ONE' which is contained within this thesis.; Amanda L Fuchs was an author, and Brian P. Tripet, Martin Teintze, Mary Cloud B. Ammons and Valerie Copié were co-authors of the article, 'Allicin identified as the principal antimicrobial compound in 1,000-year-old Bald's eyesalve' submitted to the journal 'International journal of antimicrobial agents' which is contained within this thesis.; Abigail Van Vuren, Martin Teintze, Valerie Copié and Jovanka Voyich were co-authors of the article, 'Treatment of MRSA with 18-beta-glycyrrhetinic acid reduces cell-to-cell interactions & increases production of staphyloxanthin' submitted to the journal 'Antimicrobial agents & chemotherapy' which is contained within this thesis.The studies herein investigated and characterized synthetic and natural products having efficacy against methicillin-resistant Staphylococcus aureus, which has become a significant threat to both hospital and community environments due to rapid drug resistance development. THAM-3 Phi G is a synthetic compound that showed initial promise as a novel antibacterial against S. aureus (MIC 2 mg/L) through membrane disruption. However, following sub-lethal dosing with THAM-3 Phi G, S. aureus was shown to develop resistance through a small colony variant phenotype, which was defined through 1D 1H NMR metabolomics. Natural products from age-old remedies having efficacy against S. aureus were also investigated in this study. Bald's Eyesalve has shown efficacy against S. aureus; however, the active antibacterial agent(s) remained unknown. Through molecular size and solvent fractionation, activity was isolated to the small (< 3 kDa), non-polar molecule fraction which lost activity following cysteine treatment. Following NMR spectral analysis, the organosulfur garlic-derived compound, allicin, was identified as the active antimicrobial agent. GRA is a natural product found in licorice root, which was used in ancient Chinese medicine. GRA is known to have efficacy against S. aureus and to downregulate key virulence genes. Prolonged exposure of S. aureus to GRA revealed significant increases in the pigment staphyloxanthin. Furthermore, NMR metabolomics of short-term treatments revealed a dysregulation of the TCA cycle, which collectively suggests that treatment of S. aureus with GRA results in oxidative stress. The efficacy of GRA against S. aureus biofilms was also investigated and showed GRA to be ineffective at reducing biofilm CFUs; however, GRA effected biofilm stability. Planktonic studies revealed significant reductions in cell-to-cell interactions beginning at 7.8 mg/L GRA based on optical density measurements and microscopy. Therefore, GRA may serve as part of a novel therapeutic method for treating chronic wound infections. Collectively, these studies utilized NMR to define metabolic phenotypes of bacteria in response to drug treatment and to resolve the active agent in a complex mixture of an age-old remedy. While S. aureus was able to overcome the antibacterial activity of THAM-3 Phi G, the studies of natural products from age-old remedies may provide future treatment options that require further investigation.Item Modeling biofilm antimicrobial resistance(Montana State University - Bozeman, College of Engineering, 1998) Dodds, Michael GrantItem Measuring antimicrobial efficacy against sulfate-reducing bacterial biofilms(Montana State University - Bozeman, College of Engineering, 1999) Gardner, Lawrence RobertItem Physiological basis for biofilm resistance to antimicrobial agents(Montana State University - Bozeman, College of Agriculture, 1998) Cochran, Wendy LeeItem Investigation of biofilm resistance to antimicrobial agents(Montana State University - Bozeman, College of Engineering, 1999) Grobe, Katherine Jean