Staphylococcus aureus is the leading cause of bacterial keratitis in the United States. Staphylococcus is a challenging organisms because of its virulence and its propensity to constantly evolve to new states of antibiotic- resistance. To cope with the increased drug-resistance, vancomycin, a slow- acting and more toxic antibiotic, must often be used. New antimicrobial therapy for Staphylococcus keratitis is needed at this time. Another limitation to treatment of keratitis is that no therapy presently available will stop the toxic bacterial reactions that damage the cornea and trigger the host reactions responsible for scarring. The long term objective of this research proposal is to develop potent antimicrobial therapy and to prevent the issue damaging reactions associated with Staphylococcus keratitis. Recent research from the laboratory has identified the toxin, alpha-toxin, most frequently responsible for these harmful reactions. Thus the proposed research will test the hypotheses concerning frequently responsible for these harmful reactions. Thus, the proposed research will test hypotheses concerning the protectiveness of augmented immune reactions to arrest alpha-toxin-mediated tissue damage, the effectiveness of a powerful new antimicrobial agent, as well as further analyses of staphylococcus toxins active during keratitis. The proposed research will pursue the following aims: 1) develop immunologic mens to prevent alpha-toxin action or its synthesis; 2) analyze the action of a novel chemotherapeutic agent with rapid bactericidal activity as a therapy for experimental Staphylococcus keratitis; 3) establish that a new Staphylococcus toxin can mediate corneal damage and determine how commonly (estimated 25%) the new toxin is involved in keratitis; and 4) develop an intra-corneal genetic expression system to allow analysis of individual bacterial proteins as tissue-damaging toxins or as vaccines. These proposed studies offer realistic hope for developing therapy to prevent the blinding consequences of Staphylococcus keratitis.
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