Unlocking the Potential of Bacterial ParE Toxins: Developing a Blueprint for Co-Opting Molecular Time Bombs That Impact Bacterial Cell Survival
Abstract
This project aims to “Unlock[ing] the potential of bacterial ParE toxins: developing a blueprint for coopting 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. This proposal is responsive to the Topic Area of “Antimicrobial Resistance”. When successful, this will provide an innovative new way to control bacterial growth, including antibacterial resistant strains. The particular bacterial protein that is being targeted in this strategy, a component of a “toxin-antitoxin” system, is known to inhibit bacterial cell replication. In the process of this inhibition, the protein induces double-strand DNA breaks. Accumulation of these breaks will result in bacterial cell death, which is an overall objective of the proposal. However, the number of breakage events, which are correlated with the amount of the ParE protein produced, that are needed is not known and will be tested in this study. This proposal also addresses co-treatment options, whereby the combination of double-strand DNA breaks with current treatments will make existing antibiotics more useful. A smaller number of DNA breaks can theoretically initiate well-known error-prone repair pathways. These error-prone repair events are directly implicated in the formation of antibiotic resistance. Therefore, this study includes experiments to measure the contribution of this bacterial ParE protein in the development of genetic changes leading to resistance. Currently there is no link between toxin-antitoxin systems such as these ParE proteins and the propensity of a bacterial cell to become resistant; making this connection would dramatically shift the thinking behind how antibiotic resistance can emerge. These ParE proteins are widespread in bacteria, and each varies from the other in sequence and potentially in how potently they function. Because of these variations, the endpoint application would be specific for a given species of bacteria. This is a very important component of the innovation of this approach, as ideally the normally “good” bacteria found in patients would be spared. This good bacteria is known to increase healing time and treatment outcomes. We are focusing this study on ParE proteins from bacteria relevant for bacterial infections found in the community and over-represented in military personnel due to a number of factors, including traumatic injury.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010121
Entities
People
- Christina R Bourne
Organizations
- United States Army
- University of Oklahoma