title: Activators of cylindrical proteases as antimicrobials: identification and development of small molecule activators of ClpP protease.
abstract: ClpP is a cylindrical serine protease whose ability to degrade proteins is regulated by the unfoldase ATP-dependent chaperones. ClpP on its own can only degrade small peptides. Here, we used ClpP as a target in a high-throughput screen for compounds, which activate the protease and allow it to degrade larger proteins, hence, abolishing the specificity arising from the ATP-dependent chaperones. Our screen resulted in five distinct compounds, which we designate as Activators of Self-Compartmentalizing Proteases 1 to 5 (ACP1 to 5). The compounds are found to stabilize the ClpP double-ring structure. The ACP1 chemical structure was considered to have drug-like characteristics and was further optimized to give analogs with bactericidal activity. Hence, the ACPs represent classes of compounds that can activate ClpP and that can be developed as potential novel antibiotics.
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Elisa
authors.initials: E
authors.lastname: Leung
authors.forename: Alessandro
authors.initials: A
authors.lastname: Datti
authors.forename: Michele
authors.initials: M
authors.lastname: Cossette
authors.forename: Jordan
authors.initials: J
authors.lastname: Goodreid
authors.forename: Shannon E
authors.initials: SE
authors.lastname: McCaw
authors.forename: Michelle
authors.initials: M
authors.lastname: Mah
authors.forename: Alina
authors.initials: A
authors.lastname: Nakhamchik
authors.forename: Koji
authors.initials: K
authors.lastname: Ogata
authors.forename: Majida
authors.initials: M
authors.lastname: El Bakkouri
authors.forename: Yi-Qiang
authors.initials: YQ
authors.lastname: Cheng
authors.forename: Shoshana J
authors.initials: SJ
authors.lastname: Wodak
authors.forename: Bryan T
authors.initials: BT
authors.lastname: Eger
authors.forename: Emil F
authors.initials: EF
authors.lastname: Pai
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Scott
authors.initials: S
authors.lastname: Gray-Owen
authors.forename: Robert A
authors.initials: RA
authors.lastname: Batey
authors.forename: Walid A
authors.initials: WA
authors.lastname: Houry
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D003198:Computer Simulation; D049071:Endopeptidase Clp / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004926:Escherichia coli / Q000201:enzymology; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D018832:Molecular Chaperones / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins; D018832:Molecular Chaperones; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D049071:Endopeptidase Clp