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Title page for ETD etd-11212006-082620

Type of Document Master's Thesis
Author Grandillo, Jessica Louise
URN etd-11212006-082620
Title Structural and Mechanistic Observations of the FosX Class of Fosfomycin Resistance Proteins
Degree Master of Science
Department Biochemistry
Advisory Committee
Advisor Name Title
Dr. Richard Armstrong Committee Chair
Dr. Daniel Liebler Committee Member
  • hydrogen-deuterium exchange mass spectrometry
  • antibiotic resistance
  • optical spectroscopy
  • protein purification
  • gene expression
  • Fosfomycin
  • Drug resistance in microorganisms
  • Hydrolases -- Analysis
Date of Defense 2006-11-21
Availability unrestricted
The objective of this research was to investigate the structure and catalytic mechanisms of the FosX protein class. These enzymes are epoxide hydrolases that disrupt the first step of bacterial cell wall biosynthesis, thereby inactivating the antibiotic fosfomycin. Data presented in this work concerns FosX enzymes from the genome of pathogenic microorganism Listeria monocytogenes and a recently discovered integron isolated from Pseudomonas putida. Hydrogen-deuterium exchange mass spectrometry was used to determine structural perturbations that occur when the Listeria protein binds to divalent metal species. In addition, steady-state metal binding to Listeria FosX was investigated using optical spectroscopy. Finally, the putative FosX gene from Pseudomonas was cloned and the protein product expressed and purified. The enzyme was tested for FosX activity and ability to confer fosfomycin resistance. The ultimate goal of this research is to elucidate further mechanistic details about this class of fosfomycin resistance proteins, with the hope to one day develop inhibitors that will lessen or eliminate bacterial resistance to this antibiotic.
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