title: Glycylcyclines bind to the high-affinity tetracycline ribosomal binding site and evade Tet(M)- and Tet(O)-mediated ribosomal protection.
abstract: N,N-dimethylglycylamido (DMG) derivatives of 6-demethyl-6-deoxytetracycline and doxycycline bind 5-fold more effectively than tetracycline to the tetracycline high-affinity binding site on the Escherichia coli 70S ribosome, which correlates with a 10-fold increase in potency for inhibition of E. coli cell-free translation. The potencies of DMG-doxycycline and DMG-6-demethyl-6-deoxytetracycline were unaffected by the ribosomal tetracycline resistance factors Tet(M) and Tet(O) in cell-free translation assays and whole-cell bioassays with a conditional Tet(M)-producing E. coli strain.
authors.affiliation: Central Research Division, Pfizer Inc., Groton, Connecticut 06340, USA.
authors.forename: J
authors.initials: J
authors.lastname: Bergeron
authors.forename: M
authors.initials: M
authors.lastname: Ammirati
authors.forename: D
authors.initials: D
authors.lastname: Danley
authors.forename: L
authors.initials: L
authors.lastname: James
authors.forename: M
authors.initials: M
authors.lastname: Norcia
authors.forename: J
authors.initials: J
authors.lastname: Retsema
authors.forename: C A
authors.initials: CA
authors.lastname: Strick
authors.forename: W G
authors.initials: WG
authors.lastname: Su
authors.forename: J
authors.initials: J
authors.lastname: Sutcliffe
authors.forename: L
authors.initials: L
authors.lastname: Wondrack
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism* / Q000494:pharmacology; D001681:Biological Assay; D002474:Cell-Free System; D004318:Doxycycline / Q000494:pharmacology; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D006033:Glycylglycine / Q000378:metabolism*; D010452:Peptide Biosynthesis; D012270:Ribosomes / Q000378:metabolism*; D013753:Tetracycline Resistance / Q000235:genetics / Q000502:physiology*
chemical_list: D000900:Anti-Bacterial Agents; D006033:Glycylglycine; D004318:Doxycycline