Chemically related 4,5-linked aminoglycoside antibiotics drive subunit rotation in opposite directions

Nat Commun. 2015 Jul 30;6:7896. doi: 10.1038/ncomms8896.

Abstract

Dynamic remodelling of intersubunit bridge B2, a conserved RNA domain of the bacterial ribosome connecting helices 44 (h44) and 69 (H69) of the small and large subunit, respectively, impacts translation by controlling intersubunit rotation. Here we show that aminoglycosides chemically related to neomycin-paromomycin, ribostamycin and neamine-each bind to sites within h44 and H69 to perturb bridge B2 and affect subunit rotation. Neomycin and paromomycin, which only differ by their ring-I 6'-polar group, drive subunit rotation in opposite directions. This suggests that their distinct actions hinge on the 6'-substituent and the drug's net positive charge. By solving the crystal structure of the paromomycin-ribosome complex, we observe specific contacts between the apical tip of H69 and the 6'-hydroxyl on paromomycin from within the drug's canonical h44-binding site. These results indicate that aminoglycoside actions must be framed in the context of bridge B2 and their regulation of subunit rotation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aminoglycosides / metabolism
  • Aminoglycosides / pharmacology*
  • Anti-Bacterial Agents / metabolism
  • Anti-Bacterial Agents / pharmacology*
  • Binding Sites
  • Escherichia coli
  • Escherichia coli Proteins / drug effects
  • Escherichia coli Proteins / metabolism
  • Framycetin / metabolism
  • Framycetin / pharmacology
  • Neomycin / metabolism
  • Neomycin / pharmacology
  • Paromomycin / metabolism
  • Paromomycin / pharmacology
  • RNA, Bacterial / drug effects*
  • RNA, Bacterial / metabolism
  • Ribosome Subunits, Large, Bacterial / drug effects*
  • Ribosome Subunits, Large, Bacterial / metabolism
  • Ribosome Subunits, Small, Bacterial / drug effects*
  • Ribosome Subunits, Small, Bacterial / metabolism
  • Ribosomes / drug effects
  • Ribosomes / metabolism
  • Ribostamycin / metabolism
  • Ribostamycin / pharmacology
  • Rotation

Substances

  • Aminoglycosides
  • Anti-Bacterial Agents
  • Escherichia coli Proteins
  • RNA, Bacterial
  • Ribostamycin
  • Framycetin
  • neamine
  • Paromomycin
  • Neomycin