Glycylcyclines bind to the high-affinity tetracycline ribosomal binding site and evade Tet(M)- and Tet(O)-mediated ribosomal protection.
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.
Bergeron
J
J
Central Research Division, Pfizer Inc., Groton, Connecticut 06340, USA.
Ammirati
M
M
Danley
D
D
James
L
L
Norcia
M
M
Retsema
J
J
Strick
C A
CA
Su
W G
WG
Sutcliffe
J
J
Wondrack
L
L
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*
D000900:Anti-Bacterial Agents; D006033:Glycylglycine; D004318:Doxycycline