Dysregulation of bacterial proteolytic machinery by a new class of antibiotics

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.