Chlamydia trachomatis is an impressive cause of sexually transmitted infectious disease. Numerically, it is the single leading cause of sexually transmitted infection in the United States, resulting in 3 to 4 million cases per year. C. trachomatis tends to infect adolescents and young adults. In addition, it often produces subclinical and repeat infections. This would not be quite so worrisome were it not for the tendency of chlamydial infections to result in significant long-term sequelae. Chronic pelvic pain, tubal infertility, chronic salpingitis, and ectopic pregnancy are the deleterious consequences experienced by women who have had chlamydial infections. Topical microbicides against chlamydial infection would provide a mechanism for intercepting this sequence of events. The antibiotic effects against Chlamydia of some exciting new antibiotic peptides, the protegrins, are here described. Antibiotic peptides appear to serve as """"""""natural"""""""" antimicrobials in PMNs from a number of animal species. The defensins typically contain 29-35 amino acid residues with sex invariant cysteines essential to disulfide bond formation. Protegrins are a newly recognized group of antibiotic peptides with 16-18 amino acids which have broad-spectrum activity against bacteria, fungi, and some viruses. The preliminary data indicate that the anti- chlamydial effect of protegrin is also significant, even at very low concentrations. Protegrin appears to inhibit chlamydial infection even in the presence of serum, a common genital site component. C. trachomatis is thus an excellent signal pathogen for e valuating the efficacy of these new antibiotic peptides. This proposal will test the efficacy of protegrins against Chlamydia in all the areas specifically requested. it is designed in three levels designated as the three Specific Aims: 1) in vitro assessment of antibiotic peptide activity against C. trachomatis, 2) in vivo evaluation of the influence of antibiotic peptides on C. trachomatis infection in a mouse model, and 3) assessment of toxicological effects of the antibiotic peptides on the genital tract and systemically. The in vitro testing will establish which protegrin candidates have efficacy at low concentrations in the presence of various tissue-specific components. Standard in vitro culture techniques are effective demonstrators of potential, as has been shown in the preliminary data. The in vivo testing will be performed in a preliminary data. The in vivo testing will be performed in a previously-described mouse model, using human genital strains of Chlamydia. This will allow selection of candidates which perform in a multi-factorial setting. Finally, the direct toxicological effect of the best antibiotic peptides will be analyzed by pathology and body fluid chemistry as observed in the mouse model. By these means, new antibiotic peptide candidates can be efficiently screened and selected for their efficacy against the important sexually transmitted bacterium, Chlamydia trachomatis.
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