The worldwide epidemic of sexually transmitted disease is threatening, especially to young adults. New female-controlled strategies for preventing STDs are needed urgently. Also needed are more effective means of managing bacterial vaginitis/vaginosis (BV) - a common condition of unknown cause, that increases the likelihood of upper genitourinary tract infections. This proposal is based on the discovery that protegrins, a recently described class of antibiotic peptides inactivate the elementary bodies (Ebs) of Chlamydia trachomatis, kill N. gonorrhoeae and H. ducreyii, and also protect cells from infection by HIV-1. Our previous studies defined the essential structural features of protegrins needed for activity against chlamydia EBS, gonococci and C. albicans. We now propose to """"""""fine tune"""""""" the protegrin design. By this process, we expect to generate protegrins that will kill the major bacterial STD pathogens and protect cells from HIV-1 uptake, without affecting normal vaginal Lactobacilli. Preliminary data show that this can be accomplished by replacing selected key amino acid residues. Our two specific aims are essential components of the overall plan to design a protegrin molecule with optimal properties.
Specific Aim 1. We will test the susceptibility of bacteria (Gardnerella vaginalis, Mobiluncus, Prevotella, Bacteroides, etc.) typically associated with bacterial vaginosis (BV) to synthetic protegrins and to selected peptides. The BV microorganisms to be tested will include: These studies will focus on protegrins with little or no effect against Lactobacillus sp.
Specific Aim 2. We will examine the sensitivity of C. trachomatis Ebs to protegrins and to selected peptides. In addition to testing pure cultures of archival vaginal isolates, we will test protegrins and other antimicrobial peptides on fresh clinical isolates that will be obtained from normal women and subjects with BV. Since these studies will be closely coordinated with an examination of vaginal antimicrobial polypeptides, they can also provide important insights into the pathogenesis of bacterial vaginosis.
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