title: Antibiotic acyldepsipeptides activate ClpP peptidase to degrade the cell division protein FtsZ.
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.
authors.affiliation: Institute of Medical Microbiology, Immunology, and Parasitology, Pharmaceutical Microbiology Unit, University of Bonn, 53115 Bonn, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Sass
authors.forename: Michaele
authors.initials: M
authors.lastname: Josten
authors.forename: Kirsten
authors.initials: K
authors.lastname: Famulla
authors.forename: Guido
authors.initials: G
authors.lastname: Schiffer
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Sahl
authors.forename: Leendert
authors.initials: L
authors.lastname: Hamoen
authors.forename: Heike
authors.initials: H
authors.lastname: Brötz-Oesterhelt
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D024881:Drug Resistance, Bacterial; D049071:Endopeptidase Clp / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013296:Streptococcus pneumoniae / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D003598:Cytoskeletal Proteins; C071525:FtsZ protein, Bacteria; D009842:Oligopeptides; D049071:Endopeptidase Clp