Análisis molecular, bioquímico y estructural de la ß-lactamasa de espectro extendido PER-2 : participación de aminoácidos específicos en la interacción con sustratos e inhibidores
PER-2 has been the second most prevalent acquired extended spectrum ß-lactamase in clinical isolates of enterobacteria in Argentina. Even if natural mutants of PER-2 have not yet been reported, constant selective pressure posed by the extensive antibiotic and inhibitors use, and the known evolutiona...
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| Formato: | Tesis doctoral acceptedVersion |
| Lenguaje: | Español |
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Facultad de Farmacia y Bioquímica
2016
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| Acceso en línea: | http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=posgraafa&cl=CL1&d=HWA_2002 http://repositoriouba.sisbi.uba.ar/gsdl/collect/posgraafa/index/assoc/HWA_2002.dir/2002.PDF |
| Aporte de: |
| Sumario: | PER-2 has been the second most prevalent acquired extended spectrum ß-lactamase in clinical isolates of enterobacteria in Argentina. Even if natural mutants of PER-2 have not yet been reported, constant selective pressure posed by the extensive antibiotic and inhibitors use, and the known evolutionary outcomes for other ?-lactamase families, we wondered about the actual possibility to evolve by point mutations that further improve or modify its catalytic efficiency and/or decrease susceptibility to inhibitors. By means of in silico modeling, we observed that Arg220 in PER-2 is located at equivalent spatial position than Arg244 in TEM-1/SHV-1. As inhibitor resistant TEM/SHV can arise by single mutations in this residue, we postulated that similar behavior can be obtained by mutations at Arg220 in PER-2. We also hypothesize that Thr237 can also play important role due to its structural association with Arg220. In this study, we analyzed the biochemical behavior of PER-2 derived in vitro mutants at positions 220 and 237, assigning their role in the hydrolysis and inhibition of the enzyme, we solved the crystallographic structure of PER-2, and we performed a preliminary characterization of a plasmid harboring blaPER-2. |
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