Acyldepsipeptides

Acyldepsipeptides (ADEPs) are a class of natural-product antibiotics produced by actinomycetes. They are defined by a lipophilic acyl chain linked to a cyclic depsipeptide core, typically generated by nonribosomal peptide synthetases. ADEPs were identified as activators of the bacterial ClpP protease.

They bind to the proteolytic core ClpP, inducing an open, proteolytically competent conformation. This activation bypasses the need for Clp ATPases (ClpX/ClpA) and causes uncontrolled degradation of a broad subset of cytosolic proteins, ultimately leading to bacterial cell death. Because the mechanism relies on accelerating proteolysis rather than inhibiting a single enzyme, ADEPs can be active against strains resistant to other antibiotic classes.

ADEPs show potent activity against many Gram-positive bacteria, including several antibiotic-resistant pathogens, and also display activity against some mycobacteria in vitro. Activity against many Gram-negative species is limited by permeability barriers and efflux; combinations with permeabilizing agents or specific formulations have been explored.

ADEPs are produced by Actinobacteria via NRPS pathways. The acyl chain length and substitutions on the macrocycle influence ClpP activation, potency, and selectivity. A number of natural ADEPs and synthetic analogs have been described to probe the pharmacophore and improve properties.

They are primarily research tools and leads rather than approved drugs, due to pharmacokinetic and safety challenges linked to broad protease activation. Nevertheless, they illustrate a distinct antibiotic strategy by pharmacologically dysregulating essential proteases.