This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.A major factor in the emergence of antibiotic resistance is the existence of bacterial enzymes that chemically modify common antibiotics. One such family of antibacterials to which there is now almost universal resistance are the aminoglycosides (eg. kanamycin, tobramycin and gentimicin). High level resistance to gentamicin in enterococci is mediated by a group of four phosphotransferases belonging to the APH(2?) sub-family of enzymes which phosphorylate at a specific hydroxyl group on the antibiotic. Structurally, the aminoglycoside phosphotransferase enzymes have a two-domain architecture resembling the catalytic subunit of the eukaryotic Ser/Thr and Tyr protein kinases. An understanding of how these enzymes bind and deactivate the aminoglycosides will provide valuable information fro the design of specific inhibitors of these enzymes. We are studying two of the APH(2?) phosphotransferases, APH(2?)-Ib from Enterococcus faecium and APH(2?)-Ic from E. gallinarum. The APH(2?)-Ib structure has been determined and diffraction quality crystals of APH(2?)-Ic have been grown recently, and native and derivative data have been collected.
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