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Originally published In Press as doi:10.1167/iovs.08-3157 on January 10, 2009
 (Investigative Ophthalmology and Visual Science. 2009;50:2848-2854.)
© 2009 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.08-3157
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Chemical Inhibition of Alpha-Toxin, a Key Corneal Virulence Factor of Staphylococcus aureus

Clare C. McCormick, Armando R. Caballero, Charles L. Balzli, Aihua Tang, and Richard J. O'Callaghan

From the Department of Microbiology, University of Mississippi Medical Center, Jackson, Mississippi.

PURPOSE. {alpha}-Toxin mediates extreme corneal damage during Staphylococcus aureus keratitis. Chemical inhibition of this toxin was sought to provide relief from toxin-mediated pathology.

METHODS. Inhibition of {alpha}-toxin by phosphate-buffered saline (PBS), 0.1% methyl-β-cyclodextrin (CD), or CD plus cholesterol (0.1%, CD-cholesterol) was assayed by hemolysis of rabbit erythrocytes. Pathologic changes in rabbit corneas injected with 12 hemolytic units of {alpha}-toxin suspended in PBS, 1% CD, or 1% CD-cholesterol were compared over time. Rabbit corneas injected with 102 colony forming units (CFU) of S. aureus were treated from 7 to 13 hours postinfection (PI) with a total of 15 drops of CD-cholesterol, CD, or PBS. Slit lamp examination (SLE) and measurement of erosions were performed at 13 hours PI and bacteria were quantified at 14 hours PI.

RESULTS. Toxin-mediated lysis of erythrocytes was inhibited up to 16,000-fold in the presence of CD-cholesterol compared with CD or PBS. Eyes injected with {alpha}-toxin mixed with CD-cholesterol had, at 7 hours postinjection, significantly smaller erosions than eyes injected with {alpha}-toxin in PBS or {alpha}-toxin mixed with CD (P = 0.0090 and P = 0.0035, respectively). Eyes infected with S. aureus and treated with CD-cholesterol had significantly lower SLE scores than eyes treated with CD or PBS (P ≤ 0.0103 and P ≤ 0.0017, respectively); however, there were no differences in the number of bacteria present (P ≥ 0.0648).

CONCLUSIONS. CD-cholesterol is a potent inhibitor of {alpha}-toxin activity in vitro and an effective means to arrest corneal damage during S. aureus keratitis.




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B. E. Ragle, V. A. Karginov, and J. Bubeck Wardenburg
Prevention and Treatment of Staphylococcus aureus Pneumonia with a {beta}-Cyclodextrin Derivative
Antimicrob. Agents Chemother., January 1, 2010; 54(1): 298 - 304.
[Abstract] [Full Text] [PDF]


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