Nature Medicine 11, 1082 - 1087 (2005)
Published online: 2 October 2005; | doi:10.1038/nm1306
There is a Corrigendum (December 2005) associated with this Article.
Dysregulation of bacterial proteolytic machinery by a new class of antibioticsHeike Brötz-Oesterhelt1, Dieter Beyer1, Hein-Peter Kroll1, Rainer Endermann1, Christoph Ladel1, Werner Schroeder2, Berthold Hinzen3, Siegfried Raddatz3, Holger Paulsen3, Kerstin Henninger4, Julia E Bandow5, Hans-Georg Sahl6
& Harald Labischinski11
Department of Anti-infectives, Bayer HealthCare AG, Pharma Research, Aprather Weg 18a, D-42096
Wuppertal, Germany. 2
Enabling Technologies, Bayer HealthCare AG, Pharma Research, Aprather Weg 18a, D-42096
Wuppertal, Germany. 3
Chemistry, Bayer HealthCare AG, Pharma Research, Aprather Weg 18a, D-42096
Wuppertal, Germany. 4
Pharmacokinetics, Bayer HealthCare AG, Pharma Research, Aprather Weg 18a, D-42096
Wuppertal, Germany. 5
Institute for Microbiology, University of Greifswald, F.-L.-Jahn Strasse 15, D-17487
Greifswald, Germany. 6
Institute for Medical Microbiology, University of Bonn, Sigmund-Freud-Strasse 25, D-53105
Bonn, Germany. Present addresses: RBM Serono, Via Ribes1, 10010 Colleretto Giacosa, Italy (C.L.). Pfizer Inc., Global Research and Development, Ann Arbor, Michigan
48105, USA (J.E.B.). Combinature Biopharm AG, Robert-Roessle-Str. 10, Berlin, Germany (H.L.).
Correspondence should be addressed to Heike Brötz-Oesterhelt heike.broetz-oesterhelt@bayerhealthcare.com 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.
MORE ARTICLES LIKE THIS These links to content published by NPG are automatically generated.
|
