Identification of a compound that disrupts the primosome function in Neisseria gonorrhoeae DNA replication restart
Michael A. Jones
Download Project (297 KB)
Neisseria gonorrhoeae, the causative agent of gonorrhea, is a gram negative pathogen. Due to its highly adapted genome, this pathogen elicits resistance to the oxidative damaging agents released by neutrophils of an infected host. During DNA replication, DNA damage contributes to genome instability that hinders the progression of the replisome. Furthermore, the bacterial genome happens to be one of the important targets of these damaging agents. However, studies indicate that DNA replication restart pathways provide bacterial cells with a mechanism to reactivate replisomes that have been disrupted in this way. In N. gonorrhoeae, DNA replication restart is a process carried out by the primosome proteins PriA and PriB. The first part of my research contributed to understanding the features of this pathway. Evidence that PriA plays an essential role in resisting the toxic effects of oxidative damaging agents enhances the importance of DNA replication restart pathway for the survival of this infectious bacterium. Developing antibacterial agents that affect this pathway could be an essential discovery in the field of medicine. In this process, an enzyme based assay was developed to use in high-throughput screening to identify potential compounds that inhibit the DNA replication restart pathway in N. gonorrhoeae. An initial screening of over several thousand compounds has produced several lead compounds that may potentially block this pathway. I worked with two of the lead compounds, penicillin G potassium salt and paroxetine hydrochloride hemihydrate, and here I report the mechanism by which paroxetine disrupts the DNA replication restart pathway.
Matthew E. Lopper
Primary Advisor's Department
Stander Symposium project
"Identification of a compound that disrupts the primosome function in Neisseria gonorrhoeae DNA replication restart" (2013). Stander Symposium Projects. 276.