title: Dysregulation of bacterial proteolytic machinery by a new class of antibiotics.
abstract: Here we show that a new class of antibiotics-acyldepsipeptides-has antibacterial activity against Gram-positive bacteria in vitro and in several rodent models of bacterial infection. The acyldepsipeptides are active against isolates that are resistant to antibiotics in clinical application, implying a new target, which we identify as ClpP, the core unit of a major bacterial protease complex. ClpP is usually tightly regulated and strictly requires a member of the family of Clp-ATPases and often further accessory proteins for proteolytic activation. Binding of acyldepsipeptides to ClpP eliminates these safeguards. The acyldepsipeptide-activated ClpP core is capable of proteolytic degradation in the absence of the regulatory Clp-ATPases. Such uncontrolled proteolysis leads to inhibition of bacterial cell division and eventually cell death.
authors.affiliation: Department of Anti-infectives, Bayer HealthCare AG, Pharma Research, Aprather Weg 18a, D-42096 Wuppertal, Germany. heike.broetz-oesterhelt@bayerhealthcare.com
authors.forename: Heike
authors.initials: H
authors.lastname: Brötz-Oesterhelt
authors.forename: Dieter
authors.initials: D
authors.lastname: Beyer
authors.forename: Hein-Peter
authors.initials: HP
authors.lastname: Kroll
authors.forename: Rainer
authors.initials: R
authors.lastname: Endermann
authors.forename: Christoph
authors.initials: C
authors.lastname: Ladel
authors.forename: Werner
authors.initials: W
authors.lastname: Schroeder
authors.forename: Berthold
authors.initials: B
authors.lastname: Hinzen
authors.forename: Siegfried
authors.initials: S
authors.lastname: Raddatz
authors.forename: Holger
authors.initials: H
authors.lastname: Paulsen
authors.forename: Kerstin
authors.initials: K
authors.lastname: Henninger
authors.forename: Julia E
authors.initials: JE
authors.lastname: Bandow
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Sahl
authors.forename: Harald
authors.initials: H
authors.lastname: Labischinski
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000145:classification* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D001412:Bacillus subtilis / Q000187:drug effects; D001419:Bacteria / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D047630:Depsipeptides / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D024901:Drug Resistance, Multiple, Bacterial; D049071:Endopeptidase Clp / Q000378:metabolism*; D004926:Escherichia coli / Q000187:drug effects; D029968:Escherichia coli Proteins / Q000378:metabolism*; D005260:Female; D051379:Mice; D015394:Molecular Structure; D009154:Mutation; D011008:Pneumococcal Infections / Q000188:drug therapy / Q000382:microbiology; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D051381:Rats; D017208:Rats, Wistar; D018805:Sepsis / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000900:Anti-Bacterial Agents; D047630:Depsipeptides; D029968:Escherichia coli Proteins; C483572:ClpP protease, E coli; D049071:Endopeptidase Clp