Theses and Dissertations at Montana State University (MSU)
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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.