Unlocking the Potential of Bacterial ParE Toxins: Developing a Blueprint for Co-opting Molecular Time Bombs that Impact Bacterial Cell Survival

This project aims to Unlock[ing] the potential of bacterial ParE toxins: developing a blueprint for co-opting molecular time bombs that impact bacterial cell survival. The central problem addressed by the aims is of treating bacterial infections with an outcome of making existing antibiotics work better, and in understanding a fundamental bacterial mechanism that may help bacteria become resistant. When successful, this will provide an innovative new way to control bacterial growth, including antibacterial resistant strains. During this reporting period we have constructed reagents needed to determine which of the ParE proteins in two pathogenic bacteria have the greatest impact on bacterial cell survival. These assays revealed that of two different ParE toxins in each bacteria tested to date, only one of them is potently toxic and likely to be useful for an antibacterial approach. The other ParE toxins, which display limited impacts on viability, either are not functional or may promote survival by activating pathways for mutagenesis. If the later, this could be an important component of how antibiotic resistance develops. These important first identification steps will allow us to pursue our end goals by targeting the most toxic ParE proteins while ensure the potentially mutation-driving ParE toxin proteins are not manipulated.