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T. Suzuki, J. G. Swoboda, J. Campbell, S. Walker, M. S. Gilmore; Efficacy of Wall Teichoic Acid Biosynthesis Inhibitor in Ocular Infection Caused by Staphylococcus Aureus. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5714.
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© ARVO (1962-2015); The Authors (2016-present)
Antibiotic resistant microbes, including methicillin resistant Staphylococcus aureus (MRSA), have become leading agents of keratitis or endophthalmitis. Thus new strategies for treatment and prevention are needed. Wall teichoic acids (WTAs) are major polyanionic polymers in the cell wall of Staphylococcus aureus. We demonstrated WTAs are important for the full manifestation of virulence by S. aureus in ocular infection in ARVO 2009. A new bacteriostatic compound (1835F03) that inhibits WTA biosynthesis and growth was recently identified. This study was designed to determine whether WTA biosynthesis represents a useful target for a new prophylactic or therapeutic agent.
Minimum inhibitory concentrations (MIC) of 1835F03 were determined according to CLSI protocols for S. aureus keratitis isolates. This compound was assessed for toxicity against human cultured corneal epithelial cells (HCEC), and investigated to determine its activity for inhibiting bacterial invasion. To determine the efficacy of 1835F03 in vitro, S. aureus strains was cultured in bovine vitreous humor with 1835F03. Additionally, the virulence of 1835F03 resistant mutants (5,000 CFU) was tested in C57B6 mouse endophthalmitis. Changes in electroretinography (ERG) and histopathology were determined.
MIC range for 1835F03 were between 2 and 8 µg/mL against keratitis isolates including MRSA. At concentrations above the MIC, 1835F03 did not induce HCEC damage, and significantly reduced bacterial internalization by HCEC. Furthermore 1835F03 was found to be bactericidal in vitreous. Eyes inoculated with 1835F03 resistant mutants retained significantly greater B-wave amplitude per ERG than eyes infected with the wild type parental. Histological examination showed that the retina was not destroyed in the eyes infected with 1835F03 resistant mutants, indicating that they are highly attenuated.
The WTA biosynthesis pathway of S. aureus is a viable target for treatment and prevention of keratitis and endophthalmitis caused by S. aureus.
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