Date of Thesis Acceptance
Major Department or Program
Biochemistry, Biophysics and Molecular Biology
The dramatically increasing number of bacterial pathogens acquiring antimicrobial resistance (AMR) and multidrug resistance (MDR) poses a threat to our nation’s health and security. When these bacteria have the potential to be used intentionally as biological warfare agents (BWAs), the danger is amplified. To mitigate the potential threat of MDR in pathogens with the capacity for weaponization, non-pathogenic MDR surrogates are being generated and they will be used to understand the genomic evolution towards antibiotic resistance. Bacillus anthracis (causative agent of anthrax) and Yersinia pestis (causative agent of the plague) are two such bacteria that have been weaponized in the past and still are potentially weaponizable. In September 2001, the “Amerithrax” terrorist attack utilized refined spores of B. anthracis, targeting media institutions and government officials, resulting in 22 confirmed cases of anthrax and bringing concerns of BWAs to the forefront. Y. pestis, responsible for the death of half of Europe’s population during The Black Death, lends itself to aerosolization and can also be used to infect large numbers of individuals. Clearly, the continued acquisition of AMR/MDR, through natural or artificial means, by these and other pathogens, greatly reduces the efficacy of our diminishing array of antimicrobial treatments. Three surrogate pathogens, B. anthracis Sterne and Y. pestis KIM6 and KIM10, were used to evolve strains resistant to various antibiotics. Surrogates permit safe laboratory analysis of the genetic progression toward AMR/MDR, as well as testing of various novel candidate drugs without the need for highly regulated and costly select agent and/or biosafety level 3 facilities. Bacteria were subjected to selective pressures on plates containing three times the initial minimum inhibitory concentration of specific antibiotics. Resistant mutants were isolated and used for subsequent selection rounds on other antibiotics. To verify the presence and evolution of genes conferring resistance, the AMR/MDR surrogate isolates will be sequenced using high throughput whole genome sequencing, and then the surrogate isolates will be compared to the sequences of their parent strains. The generated AMR/MDR strains will form a validated panel that can be used in reference laboratories to test new therapeutics.
Bacillus anthracis‚ Yersinia pestis‚ Pathogenic microorganisms‚ Pathogenic microorganisms -- Surrogate‚ Drug resistance in microorganisms‚ Multidrug resistance‚ Biological warfare‚ Anthrax‚ Black Death‚ Science‚ Whitman College 2018 -- Dissertation collection -- Biochemistry, Biophysics, and Molecular Biology
Whitman Community Accessible Thesis
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