This R21/R33 phased project will explore a novel strategy for combating sexually transmitted chlamydial and gonococcal infections. Chlamydia trachomatis and Neisseria gonorrhoeae are the most common sexually transmitted pathogens. In addition to acute urogenital inflammation, chlamydial and gonococcal infections frequently result in devastating complications including infertility and chronic pelvic pain syndrome. Infection with these bacteria also increases the risk of HIV infection. Sexually transmitted chlamydial and gonococcal infections disproportionately affect the wellness of women. Therefore, there is an urgent need to develop effective self-administered topical antimicrobials to combat the transmission of these organisms and other sexually transmitted pathogens. We have discovered that C. trachomatis and N. gonorrhoeae are highly susceptible to inhibitors of peptide deformylase (PDF), an enzyme that catalyzes the removal of the formyl group from newly synthesized proteins/peptides before they become biologically active. Lactobacilli and Escherichia coli are significantly resistant to PDF inhibitors. We hypothesize that PDF inhibitors may be used topically to prevent sexually transmitted chlamydial and gonococcal infections without disrupting normal microflora. The goal of the R21-phase research is to determine the feasibility of utilizing the lead PDF inhibitor LBM415 topically for combating genital chlamydial and gonococcal infections. Thus, mice will be intravaginally exposed to a commercial gel containing LBM415 to determine whether LBM415 is free of acute and long-term toxicity, and provides protection against vaginal chlamydial and/or gonococcal infections upon its topical application. In addition, the effects of LBM415 on vaginal probiotic lactobacilli and bacterial vaginosis-associated pathogens will be determined. Frequencies of resistance to LBM415 in Chlamydia trachomatis and N. gonorrhoeae will also be assessed. If the R21 research meets its defined milestones (i.e., meaningful protection against chlamydial and gonococcal infections in vivo, a lack of in vivo toxicity, significant toleration by probiotic lactobacilli and acceptable resistance frequencies), additional studies will be carried out to further determine the value of LBM415 for combating chlamydial and gonococcal infections in the R33 phase. During the R33 phase, dose-response, inhibition of pathogen shedding from animals with pre-established infection, possibility of """"""""early"""""""" application and potential synergism with another promising broad-spectrum topical microbicide candidate will be studied.
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