title: In vitro antimicrobial activity of wall teichoic acid biosynthesis inhibitors against Staphylococcus aureus isolates.
abstract: Staphylococcus aureus is the leading cause of invasive and superficial human infections, is increasingly antibiotic resistant, and is therefore the target for the development of new antimicrobials. Compounds (1835F03 and targocil) were recently shown to function as bacteriostatic inhibitors of wall teichoic acid (WTA) biosynthesis in S. aureus. To assess the value of targeting WTA biosynthesis in human infection, it was therefore of interest to verify the involvement of WTA in bacterial binding to human corneal epithelial cells (HCECs) and to assess the activities of inhibitors of WTA biosynthesis against clinical isolates of methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) from cases of human keratitis. The 1835F03 MIC(90)s were 8 μg/ml for MSSA keratitis isolates and >32 μg/ml for MRSA keratitis isolates. The MIC(90) for the analog of 1835F03, targocil, was 2 μg/ml for both MRSA and MSSA. Targocil exhibited little toxicity at concentrations near the MIC, with increased toxicity occurring at higher concentrations and with longer exposure times. Targocil activity was moderately sensitive to the presence of serum, but it inhibited extracellular and intracellular bacteria in the presence of HCECs better than vancomycin. Targocil-resistant strains exhibited a significantly reduced ability to adhere to HCECs.
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Swoboda
authors.forename: Jennifer
authors.initials: J
authors.lastname: Campbell
authors.forename: Suzanne
authors.initials: S
authors.lastname: Walker
authors.forename: Michael S
authors.initials: MS
authors.lastname: Gilmore
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D003315:Cornea / Q000166:cytology / Q000382:microbiology; D004847:Epithelial Cells / Q000382:microbiology; D006801:Humans; D007634:Keratitis / Q000382:microbiology; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000302:isolation & purification; D008826:Microbial Sensitivity Tests; D013203:Staphylococcal Infections / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000302:isolation & purification; D013329:Structure-Activity Relationship; D013682:Teichoic Acids / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
chemical_list: D000900:Anti-Bacterial Agents; D013682:Teichoic Acids