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.
Bibliographical noteFunding Information:
This work was supported by the University of Oklahoma Junior Faculty Fellowship (A.S.D.), Oklahoma Center for the Advancement of Science and Technology (OCAST, HR15-161), and University of Oklahoma start-up funding. The initial screen was partially subsidized by an Undergraduate Research Opportunity Program (UROP) Award (J.A.C.). Research reported in this publication was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM103640.