title: Design, synthesis and in vitro biological evaluation of oligopeptides targeting E. coli type I signal peptidase (LepB).
abstract: Type I signal peptidases are potential targets for the development of new antibacterial agents. Here we report finding potent inhibitors of E. coli type I signal peptidase (LepB), by optimizing a previously reported hit compound, decanoyl-PTANA-CHO, through modifications at the N- and C-termini. Good improvements of inhibitory potency were obtained, with IC50s in the low nanomolar range. The best inhibitors also showed good antimicrobial activity, with MICs in the low μg/mL range for several bacterial species. The selection of resistant mutants provided strong support for LepB as the target of these compounds. The cytotoxicity and hemolytic profiles of these compounds are not optimal but the finding that minor structural changes cause the large effects on these properties suggests that there is potential for optimization in future studies.
authors.affiliation: Uppsala University, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: De Rosa
authors.affiliation: Uppsala University, Department of Cell and Molecular Biology, BMC, Box 596, SE-751 24 Uppsala, Sweden.
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.affiliation: Uppsala University, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Edouard
authors.initials: E
authors.lastname: Zamaratski
authors.affiliation: Uppsala University, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Natalia
authors.initials: N
authors.lastname: Szałaj
authors.affiliation: Uppsala University, Department of Medical Biochemistry and Microbiology, BMC, Box 582, SE-751 23 Uppsala, Sweden.
authors.forename: Sha
authors.initials: S
authors.lastname: Cao
authors.affiliation: Uppsala University, Department of Pharmaceutical Biosciences, BMC, Box 591, SE-751 24 Uppsala, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Wadensten
authors.affiliation: Uppsala University Hospital, Department of Medical Sciences, Uppsala, Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Lenhammar
authors.affiliation: Uppsala University, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Gising
authors.affiliation: Uppsala University, Science for Life Laboratory, Department of Cell and Molecular Biology, BMC, Box 596, SE-751 24 Uppsala, Sweden.
authors.forename: Annette K
authors.initials: AK
authors.lastname: Roos
authors.affiliation: Uppsala University, Department of Medical Biochemistry and Microbiology, BMC, Box 582, SE-751 23 Uppsala, Sweden.
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Huseby
authors.affiliation: Uppsala University Hospital, Department of Medical Sciences, Uppsala, Sweden.
authors.forename: Rolf
authors.initials: R
authors.lastname: Larsson
authors.affiliation: Uppsala University, Department of Pharmaceutical Biosciences, BMC, Box 591, SE-751 24 Uppsala, Sweden.
authors.forename: Per E
authors.initials: PE
authors.lastname: Andrén
authors.affiliation: Uppsala University, Department of Medical Biochemistry and Microbiology, BMC, Box 582, SE-751 23 Uppsala, Sweden.
authors.forename: Diarmaid
authors.initials: D
authors.lastname: Hughes
authors.affiliation: Uppsala University, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Brandt
authors.affiliation: Uppsala University, Department of Cell and Molecular Biology, BMC, Box 596, SE-751 24 Uppsala, Sweden; Uppsala University, Science for Life Laboratory, Department of Cell and Molecular Biology, BMC, Box 596, SE-751 24 Uppsala, Sweden. Electronic address: Sherry.Mowbray@icm.uu.se.
authors.forename: Sherry L
authors.initials: SL
authors.lastname: Mowbray
authors.affiliation: Uppsala University, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Box 574, SE-751 23 Uppsala, Sweden. Electronic address: Anders.Karlen@orgfarm.uu.se.
authors.forename: Anders
authors.initials: A
authors.lastname: Karlén
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004926:Escherichia coli / Q000201:enzymology*; D056945:Hep G2 Cells; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D008565:Membrane Proteins; D009842:Oligopeptides; D012697:Serine Endopeptidases; C026515:type I signal peptidase
keywords: Antibacterials; Escherichia coli; Oligopeptides; Solid-phase peptide synthesis; Type I signal peptidase