sclerotiamide and paraherquamide

Caseinolytic protease P (ClpP) maintains essential roles in bacterial homeostasis. As such, both the inhibition and activation of this enzyme result in bactericidal activity, making ClpP a promising target for antibacterial drug development. Herein, we report the results of a fluorescence-based screen of ∼450 structurally diverse fungal and bacterial secondary metabolites. Sclerotiamide (1), a paraherquamide-related indolinone, was identified as the first non-peptide-based natural product activator of ClpP. Structure-activity relationships arising from the initial screen, preliminary biochemical evaluation of 1, and rationale for the exploitation of this chemotype to develop novel ClpP activators are presented.

Topics: Anti-Bacterial Agents; Biological Products; Catalysis; Endopeptidases; Indolizines; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Protein Conformation; Spiro Compounds; Structure-Activity Relationship