TAILIEUCHUNG - Báo cáo khoa học: Directed evolution of trimethoprim resistance inEscherichia coli

Directed evolution is a useful tool in the study of enzymes. It is used in this study to investigate the means by which resistance to the antibiotic trimeth-oprim develops in dihyrofolate reductase fromEscherichia coli. Mutants with clinical levels of resistance were obtained after only three generations. | ỊFEBS Journal Directed evolution of trimethoprim resistance in Escherichia coli Morgan Watson Jian-Wei Liu and David Ollis Research Schoolof Chemistry Australian National university Canberra Australia Keywords antibiotic resistance dihydrofolate reductase directed evolution trimethoprim Correspondence M. Watson Research Schoolof Chemistry Australian NationalUniversity Canberra ACT 0200 Australia Fax 61 261 250 750 Tel 61 261 258 017 E-mail watson@ Directed evolution is a useful tool in the study of enzymes. It is used in this study to investigate the means by which resistance to the antibiotic trimethoprim develops in dihyrofolate reductase from Escherichia coli. Mutants with clinical levels of resistance were obtained after only three generations. After four generations of directed evolution several mutants were characterized along with some point mutants made to investigate amino acid changes of interest. Several mutations were found to grant resistance to trimethoprim both by reducing the binding affinity of the enzyme for the drug and by increasing the activity of the enzyme. Received 2 January 2007 revised 12 March 2007 accepted 22 March 2007 doi Naturally occurring enzyme inhibitors are found in every living organism serving purposes ranging from the regulation of metabolism to weapons against competitors predators and prey. By contrast artificial enzyme inhibitors serve two primary purposes to aid the study of enzymes and biological pathways and to serve as drugs in medical applications 1 . The synergy between these two approaches is well illustrated when examination of the means by which an enzyme becomes resistant to an antagonist furthers our understanding of the functionality of the enzyme itself. However the study of the mechanistic relationship between inhibition by antibacterials and enzymatic activity is complicated by the systematic differences between susceptible and resistant forms of an enzyme. .

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