title: Sclerotiamide: The First Non-Peptide-Based Natural Product Activator of Bacterial Caseinolytic Protease P.
abstract: 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.
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Lavey
authors.forename: Jesse A
authors.initials: JA
authors.lastname: Coker
authors.affiliation: Protein Production Core, University of Oklahoma COBRE in Structural Biology , Norman, Oklahoma 73019, United States.
authors.forename: Eliza A
authors.initials: EA
authors.lastname: Ruben
authors.forename: Adam S
authors.initials: AS
authors.lastname: Duerfeldt
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001688:Biological Products / Q000737:chemistry* / Q000494:pharmacology*; D002384:Catalysis; D010450:Endopeptidases / Q000378:metabolism*; D007212:Indolizines / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D013141:Spiro Compounds / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001688:Biological Products; D007212:Indolizines; D013141:Spiro Compounds; C103459:sclerotiamide; D010450:Endopeptidases; C063985:paraherquamide