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Complete and faithful replication of a cell's genetic information is an essential process. Many enzymes are involved in the successful duplication of genetic information and the integrity of these enzymes can be compromised when they encounter DNA damage. Bacterial cells use a pathway called DNA replication restart to resume DNA replication following a disruptive encounter of the DNA replication enzymes with DNA damage. This pathway is catalyzed by primosome proteins, including PriA, PriB, PriC, DnaT, DnaB, DnaC, and DnaG. The importance of DNA replication restart for bacterial cell survival is demonstrated by the inability of strains that carry mutations in key primosome genes to grow and resist DNA damaging agents. Furthermore, this pathway is specific for bacterial cells: human cells don't use the same replication restart pathway and they don't encode genes for the primosome proteins that function in bacteria. Since DNA replication restart pathways are essential for bacterial cell growth and survival and are notably absent in human cells, we seek to answer the following question: can bacterial DNA replication restart pathways be targeted with novel antibacterial compounds? In order to answer this question, we have developed an enzyme based assay for high-throughput inhibitor screening to identify compounds that block the function of the primosome proteins PriA and PriB. Several interesting lead compounds have already been identified from the preliminary screening. In this study, the lead compounds have been validated as legitimate inhibitors and characterized with respect to their potency and mechanism of action.
Matthew E. Lopper
Primary Advisor's Department
Stander Symposium poster
Aduri, DRK Chaitanya, "Mechanistic studies of inhibitors of DNA replication restart pathways in Neisseria gonorrhea" (2013). Stander Symposium Posters. 196.