Evolution of antibiotic resistance in BlaTEM genes

Bacterial resistance has been increasing over the past 70 years in the human population (Hall and Barlow 2004). The Centers for Disease Control and Prevention state that about 13,000 patients in US hospitals have died due to bacterial diseases that conferred resistance to the antibiotic therapies and the costs of antibiotic long–term care range from $38 million to $137 million annually (CDC). Bacteria have acquired different mechanisms that enable it to become resistant to antibiotics such as common clinically prescribed β-Lactam antibiotics. Bla_TEM gene variations which code for TEM-β-Lactamases are the most prevalent mechanisms of resistance. Extended studies of different mutations on Bla_TEM genes have provided us with valuable information of resistance. The evolving mutations from bla_TEM-1 gene to bla_TEM-85 gene, a gene containing four mutations that leads to four different amino acid substitutions, provides us a model to study the evolutionary mechanisms of these naturally occurring mutations. We measured the fitness of the different alleles on the pathway from bla_TEM-1 gene to bla_TEM-85 gene to evaluate bla_TEM-1 evolutionary mechanisms. We have identified and evaluated a large amount of sign epistasis of these alleles under single drugs which help us to understand one more aspect of natural selection process guiding antibiotic resistance evolution.