Specific Inhibition of Chlamydia with Hydroxamates

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DESCRIPTION (provided by applicant): This new R21 grant will explore a novel mechanism for chlamydial infection. Chlamydiae are widespread human pathogens responsible for a variety of diseases including preventable blindness, pelvic inflammatory disease, infertility, pneumonia and arthritis. In the United States, genital chlamydial infection is the most prevalent of all sexually transmitted infections. Chlamydial infection also predisposes individuals to HIV infection. Chlamydiae are obligate intracellular bacteria, and cause pathological changes by replicating within and disrupting the cells of infected hosts, and by eliciting inflammatory reactions. The long-term goal of this project is to elucidate the pathogenesis of chlamydial disease by defining novel bacterial components essential for successful chlamydial infection and to explore a new strategy for prevention and treatment of chlamydial disease by targeting these novel components. It has been observed that the intracellular development of Chlamydiae is highly sensitive to the family of metalloprotease inhibitors referred to as hydroxamates. These inhibitors appear to have specificity for Chlamydiae since they do not affect growth of Escherichia coli and other common bacteria species. Hydroxamate treatment reversed the inhibition of cell proliferation caused by chlamydial infection. A Chlamydia trachomatis mutant designated GR10 that is highly resistant to hydroxamate treatment has been isolated. These findings suggest that a chlamydial protein that is sensitive to hydroxamates - most likely a zinc metalloprotease - is required for chlamydial infection, and may serve as an ideal target for the intervention of chlamydial infection. This research will identify the molecular target of the hydroxamic compound that is highly effective in inhibiting chlamydial growth. This project will also address whether the metalloprotease plays a role in chlamydial pathogenesis, and will further explore the utility of hydroxamic compounds for treating chlamydial infection.