Antibiotic acyldepsipeptides activate ClpP peptidase to degrade the cell division protein FtsZ
| Autor: | Hans-Georg Sahl, Guido Schiffer, Kirsten Famulla, Michaele Josten, Peter Sass, Leendert W. Hamoen, Heike Brötz-Oesterhelt |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Staphylococcus aureus
Antibiotic acyldepsipeptides Cell division Bacillus subtilis Microbiology chemistry.chemical_compound Bacterial Proteins Drug Resistance Bacterial Cytoskeleton FtsZ Multidisciplinary biology Endopeptidase Clp Biological Sciences biology.organism_classification Anti-Bacterial Agents Enzyme Activation Acyldepsipeptide antibiotics Cytoskeletal Proteins Streptococcus pneumoniae Tubulin chemistry biology.protein Oligopeptides Cell Division Bacteria |
| Zdroj: | Proceedings of the National Academy of Sciences. 108:17474-17479 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1110385108 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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