Two ways to skin a cat: acyldepsipeptides antibiotics can kill bacteria through activation or inhibition of ClpP activity.

Infection by Mycobacterium tuberculosis (Mtb) has had a devastating effect on the world population. Acyldepsipeptide antibiotics (ADEPs) are known to kill some bacteria by over activating the bacterial ClpP peptidase. ADEP antibiotics also target Mtb, with the assumption that uncontrolled ADEP-activated proteolysis by ClpP is the common mode of killing. In this issue of Molecular Microbiology, Famulla, et al. now show that ADEP's effectiveness in mycobacteria is likely due to inhibition of ClpP-dependent protease activity rather than activation. This finding of how the same antibiotic can kill bacteria by either inhibiting or activating proteases illustrates the utility of targeting these enzymes for sorely needed new antibiotics.