Microbiology: Regulation of Translation Homeostasis as a Driver of Bacterial Persistence
Abstract
Persisters are microbial cells that enter a dormant state tolerant to the action of antibiotics. Once the antibiotic is withdrawn, persisters can reactivate and resume infection, leading to relapses and chronic diseases. While persisters pose serious health issues, mechanisms underlying their formation remain poorly understood. Persisters represent a small, temporary subpopulation of biochemically inactive cells, making their study challenging. Although persister-free mutants have not been found, several genes have been identified that yield altered persister formation phenotypes. Collectively, results from studies of bacterial persistence indicate that a set of redundant pathways lead to persistence. For example, studies have revealed that polypeptide chain initiation and elongation can be altered to induce states of persistence. Despite compelling evidence, however, the mechanisms by which components of the translational machinery contribute to persistence remain to be uncovered. In particular, how aminoacyl tRNA synthetases (aaRS), which charge tRNA molecules with their cognate amino acids, can influence persistence requires further investigation. In addition to revealing how this fundamental cellular process contributes to persistence, understanding the role of translation may further disclose how multiple cellular processes are linked in the formation of persister cells. The objective of this proposal is to decipher the mechanisms by which changes in the translation machinery participate in the formation of persister states in bacteria. We will study the impact of aminoacyl-tRNA synthetase-induced changes in translation initiation, elongation and fidelity on persister formation. Furthermore, we will use new genetic approaches to modulate expression of other aaRS genes to assess the role of each enzyme in persistence. Addressing these questions will advance understanding of the mechanism of persisters formation, which is critical in identifying new strategies to overcome antibiotic tolerance and resistance.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 09, 2020
- Source ID
- W911NF2010152
Entities
People
- Michael Ibba
Organizations
- Army Contracting Command
- Ohio State University
- United States Army