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Mutation rates and the likelihood of acquired resistance: it's worse than you think

Dickey, James (2016)
Honors Thesis (39 pages)
Committee Chair / Thesis Adviser: Levin, Bruce
Committee Members: Antia, Rustom ; Dunham, Christine
Research Fields: Microbiology; Biology
Keywords: Antibiotic; Antibiotic Resistance; Bacteria; Mutation; Staphylococcus aureus; Rifampin; Fusidic Acid; Streptomycin
Program: College Honors Program, Biology
Permanent url: http://pid.emory.edu/ark:/25593/rj833

Abstract

Antibiotic resistance is an ever-growing public health concern. In acquired antibiotic resistance, the dominant population of infecting bacteria is susceptible to the treating antibiotic, and bacteria resistant to the drug emerge and ascend during the course of treatment, resulting in treatment failure. Therefore, being able to predict the likelihood that resistance will emerge during treatment of a bacterial infection is an important consideration as we try to preserve the usefulness of antibiotics. In the case of the antibiotic rifampin, which has long been associated with high rates of resistance, we suspected that resistance occurs at a higher frequency than we would normally predict. We posed the question:Can we predict the likelihood that resistance to single antibiotics will arise and ascend in vitro from estimates of the rate of mutation of resistance and the total number of cells in the culture? We developed two methods by which to predict this likelihood in Staphylococcus aureus to the antibiotics rifampin, fusidic acid, and streptomycin and tested these predications experimentally. We observed significantly higher frequencies of resistance in cultures containing rifampin. We noted a similar effect in cultures containing fusidic acid and streptomycin, but only under specific conditions. Additionally, when cultures containing antibiotics were left to incubate for several days, we noticed an accumulation of resistant mutants over time. We generated and tested a series of hypotheses to explain these higher than anticipated rates of resistance, as well as this accumulation effect.

Table of Contents

Introduction ............................................................................................................................................ 1
Materials and Methods ............................................................................................................................. 6
Equation 1 ................................................................................................................................................. 7
Equation 2 ................................................................................................................................................. 7
Results.................................................................................................................................................... 11
Table 1 ..................................................................................................................................................... 12
Figure 1 ................................................................................................................................................... 14
Figure 2 ................................................................................................................................................... 16
Figure 3 ................................................................................................................................................... 18
Table 2 ..................................................................................................................................................... 20
Discussion .............................................................................................................................................. 20
References .............................................................................................................................................. 24
Appendices .............................................................................................................................................. 27
Appendix 1 .............................................................................................................................................. 27
Appendix 2 .............................................................................................................................................. 31
Appendix 3 .............................................................................................................................................. 32

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