Dual Mode of Action for Plusbacin A 3 in Staphylococcus aureus

J Phys Chem B. 2017 Feb 23;121(7):1499-1505. doi: 10.1021/acs.jpcb.6b11039. Epub 2017 Feb 13.

Abstract

We have used C{F}, N{F}, and N{P} rotational-echo double resonance NMR to determine the location and conformation of 19F and 15N double-labeled plusbacin A3 and of double-labeled deslipo-plusbacin A3, each bound to the cell walls of whole cells of Staphyloccocus aureus grown in media containing [1-13C]glycine. The 31P is primarily in wall teichoic acid. Approximately 25% of plusbacin headgroups (the cyclic depsipeptide backbone) are in a closed conformation (N-F separation of 6 Å), while 75% are in a more open conformation (N-F separation of 12 Å). The closed headgroups have no contact with wall teichoic acid, whereas the open headgroups have a strong contact. This places the closed headgroups in hydrophobic regions of the cell wall and the open headgroups in hydrophilic regions. None of the plusbacin tails have contact with the 31P of either wall teichoic acid or the cell membrane and thus are in hydrophobic regions of the cell wall. In addition, both heads and tails of plusbacin A3 have contact with the glycyl 13C incorporated in cell-wall peptidoglycan pentaglycyl bridges and with 13C-labeled purines near the membrane surface. We interpret these results in terms of a dual mode of action for plusbacin A3: first, disruption of the peptidoglycan layer nearest to the membrane surface by closed-conformation plusbacin A3 leading to an inhibition of chain extension by transglycosylation; second, thinning and disruption of the membrane (possibly including disruption of ATP-binding cassette transporters embedded in the membrane) by open-conformation plusbacin A3, thereby leading to release of ATP to the hydrophilic regions of the cell wall and subsequent binding by plusbacin A3.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anti-Bacterial Agents / chemistry*
  • Cell Wall / chemistry*
  • Depsipeptides / chemistry*
  • Deuterium
  • Fluorine Radioisotopes
  • Hydrophobic and Hydrophilic Interactions
  • Molecular Conformation
  • Nitrogen Radioisotopes
  • Peptidoglycan / chemistry*
  • Staphylococcus aureus / chemistry

Substances

  • Anti-Bacterial Agents
  • Depsipeptides
  • Fluorine Radioisotopes
  • Nitrogen Radioisotopes
  • Peptidoglycan
  • plusbacin A3
  • Deuterium