Antibiotic acyldepsipeptides activate ClpP peptidase to degrade the cell division protein FtsZ

Peter Sass, Michaele Josten, Kirsten Famulla, Guido Schiffer, Hans Georg Sahl, Leendert Hamoen, Heike Broẗz-Oesterhelt*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

The worldwide spread of antibiotic-resistant bacteria has lent urgency to the search for antibiotics with new modes of action that are devoid of preexisting cross-resistances. We previously described a unique class of acyldepsipeptides (ADEPs) that exerts prominent antibacterial activity against Gram-positive pathogens including streptococci, enterococci, as well as multidrug-resistant Staphylococcus aureus. Here, we report that ADEP prevents cell division in Gram-positive bacteria and induces strong filamentation of rod-shaped Bacillus subtilis and swelling of coccoid S. aureus and Streptococcus pneumoniae. It emerged that ADEP treatment inhibits septum formation at the stage of Z-ring assembly, and that central cell division proteins delocalize from midcell positions. Using in vivo and in vitro studies, we show that the inhibition of Z-ring formation is a consequence of the proteolytic degradation of the essential cell division protein FtsZ. ADEP switches the bacterial ClpP peptidase from a regulated to an uncontrolled protease, and it turned out that FtsZ is particularly prone to degradation by the ADEP-ClpP complex. By preventing cell division, ADEP inhibits a vital cellular process of bacteria that is not targeted by any therapeutically applied antibiotic so far. Their unique multifaceted mechanism of action and antibacterial potency makes them promising lead structures for future antibiotic development.

Original languageEnglish
Pages (from-to)17474-17479
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number42
DOIs
Publication statusPublished - 18 Oct 2011
Externally publishedYes

Keywords

  • Divisome
  • Multidrug-resistant Staphylococcus aureus
  • Proteolysis
  • Tubulin

Fingerprint Dive into the research topics of 'Antibiotic acyldepsipeptides activate ClpP peptidase to degrade the cell division protein FtsZ'. Together they form a unique fingerprint.

Cite this