title: A Staphylococcus aureus fitness test platform for mechanism-based profiling of antibacterial compounds.
abstract: The emergence of drug-resistant bacteria coupled with the limited discovery of novel chemical scaffolds and druggable targets inspires new approaches to antibiotic development. Here we describe a chemical genomics strategy based on 245 Staphylococcus aureus antisense RNA strains, each engineered for reduced expression of target genes essential for S. aureus growth. Attenuation of gene expression can sensitize cells to compounds that inhibit the activity of a gene product or associated process. Pools of strains grown competitively in the presence of bioactive compounds generate characteristic profiles of strain sensitivities reflecting compound mechanism of action. Here, we validate this approach with a structurally and mechanistically diverse set of reference antibiotics and, in the accompanying paper in this issue of Chemistry & Biology (Huber et al., 2009), demonstrate its use in the discovery of new cell wall inhibitors.
authors.affiliation: Merck Research Laboratories, Merck & Co., Rahway, NJ 07065, USA.
authors.forename: Robert G K
authors.initials: RG
authors.lastname: Donald
authors.forename: Stephen
authors.initials: S
authors.lastname: Skwish
authors.forename: R Allyn
authors.initials: RA
authors.lastname: Forsyth
authors.forename: Jennifer W
authors.initials: JW
authors.lastname: Anderson
authors.forename: Tanya
authors.initials: T
authors.lastname: Zhong
authors.forename: Colleen
authors.initials: C
authors.lastname: Burns
authors.forename: Suzy
authors.initials: S
authors.lastname: Lee
authors.forename: Xin
authors.initials: X
authors.lastname: Meng
authors.forename: Lynn
authors.initials: L
authors.lastname: LoCastro
authors.forename: Lisa Wang
authors.initials: LW
authors.lastname: Jarantow
authors.forename: Jesus
authors.initials: J
authors.lastname: Martin
authors.forename: Sang Ho
authors.initials: SH
authors.lastname: Lee
authors.forename: Ian
authors.initials: I
authors.lastname: Taylor
authors.forename: David
authors.initials: D
authors.lastname: Robbins
authors.forename: Cheryl
authors.initials: C
authors.lastname: Malone
authors.forename: Liangsu
authors.initials: L
authors.lastname: Wang
authors.forename: Carlos S
authors.initials: CS
authors.lastname: Zamudio
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Youngman
authors.forename: John W
authors.initials: JW
authors.lastname: Phillips
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D016000:Cluster Analysis; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D010641:Phenotype; D034622:RNA Interference; D016372:RNA, Antisense / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000235:genetics / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D016372:RNA, Antisense