"Bacterial resistance to antibiotics is a major problem for global public health, but we have an incomplete understanding of the evolutionary and genetic factors that drive the spread of resistance. This proposal is motivated by the concept that some of the key processes in resistance evolution depend on the specificity of the genetic mechanisms involved, which is at present unclear. Specificity here refers to variation of the phenotypic effects of mutations across genotypes (epistasis) or environments. I will use a combination of microbial experimental evolution, DNA sequencing and evolutionary genetics to address this problem. My objectives are to: (1) quantify the specificity of antibiotic resistance mutations across different concentrations of a range of antibiotics; (2) identify genetic mechanisms that ameliorate growth defects caused by resistance mutations (compensatory adaptation) in different resistant genotypes in both the presence and absence of antibiotics; (3) test whether compensatory adaptation to the cost of one resistance mutation can also recover the cost of other resistance mutations against the same or other antibiotics. This work will improve our understanding of the genetic and evolutionary factors that drive antibiotic resistance evolution."
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