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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 antibiotics

Heike 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 Labischinski1

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.

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