title: Chemical genetic identification of peptidoglycan inhibitors potentiating carbapenem activity against methicillin-resistant Staphylococcus aureus.
abstract: Methicillin-resistant Staphylococcus aureus (MRSA) is a major nosocomial and community-acquired pathogen for which few existing antibiotics are efficacious. Here we describe two structurally related synthetic compounds that potentiate beta-lactam activity against MRSA. Genetic studies indicate that these agents target SAV1754 based on the following observations: (i) it has a unique chemical hypersensitivity profile, (ii) overexpression or point mutations are sufficient to confer resistance, and (iii) genetic inactivation phenocopies the potentiating effect of these agents in combination with beta-lactams. Further, we demonstrate these agents inhibit peptidoglycan synthesis. Because SAV1754 is essential for growth and structurally related to the recently reported peptidoglycan flippase of Escherichia coli, we speculate it performs an analogous function in S. aureus. These results suggest that SAV1754 inhibitors might possess therapeutic potential alone, or in combination with beta-lactams to restore MRSA efficacy.
authors.affiliation: Department of Infectious Diseases, Merck & Co., Rahway, NJ 07065, USA.
authors.forename: Joann
authors.initials: J
authors.lastname: Huber
authors.forename: Robert G K
authors.initials: RG
authors.lastname: Donald
authors.forename: Sang Ho
authors.initials: SH
authors.lastname: Lee
authors.forename: Lisa Wang
authors.initials: LW
authors.lastname: Jarantow
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Salvatore
authors.forename: Xin
authors.initials: X
authors.lastname: Meng
authors.forename: Ronald
authors.initials: R
authors.lastname: Painter
authors.forename: Russell H
authors.initials: RH
authors.lastname: Onishi
authors.forename: James
authors.initials: J
authors.lastname: Occi
authors.forename: Karen
authors.initials: K
authors.lastname: Dorso
authors.forename: Katherine
authors.initials: K
authors.lastname: Young
authors.forename: Young Whan
authors.initials: YW
authors.lastname: Park
authors.forename: Stephen
authors.initials: S
authors.lastname: Skwish
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Szymonifka
authors.forename: Tim S
authors.initials: TS
authors.lastname: Waddell
authors.forename: Lynn
authors.initials: L
authors.lastname: Miesel
authors.forename: John W
authors.initials: JW
authors.lastname: Phillips
authors.forename: Terry
authors.initials: T
authors.lastname: Roemer
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D015780:Carbapenems / Q000737:chemistry / Q000494:pharmacology*; D004357:Drug Synergism; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics; D010457:Peptidoglycan / Q000737:chemistry* / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D034622:RNA Interference; D016372:RNA, Antisense / Q000378:metabolism
chemical_list: C545732:2-(2-chlorophenyl)-3-(1-(2,3-dimethylbenzyl)piperidin-4-yl)-5-fluoro-1H-indole; C545731:3-(1-((2,3-dimethylphenyl)methyl)piperidin-4-yl)-1-methyl-2-pyridin-4-yl-1H-indole; D000900:Anti-Bacterial Agents; D015780:Carbapenems; D007211:Indoles; D010457:Peptidoglycan; D010880:Piperidines; D016372:RNA, Antisense