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Title: A Salmonella toxin induces persister formation via acetylation of tRNA
Author: Cheverton, Angie
ISNI:       0000 0004 5918 1926
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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Persisters have been identified in almost all free-living bacteria and many obligate intracellular pathogens. Bacterial persisters are transiently tolerant to multiple antibiotics and are thought to be responsible for recurrent infections. The formation of non-growing persisters relies on Toxin-Antitoxin (TA) modules. These are ubiquitous molecular switches controlling bacterial growth via the release of a toxin component, which reversibly interferes with an essential cellular process. Salmonella enterica serovar Typhimurium is an intracellular pathogen that forms persisters to high levels upon internalization by macrophages and relies for that on at least 14 TA modules. Of these, 3 constitute a poorly characterized TA family where the toxin contains a predicted GCN5 N- acetyltransferase domain (GNAT). In this work, I have shown that two of the GNAT TA modules, TA6 and TA8, are bona fide TA modules. Both toxins require the predicted Acetyl Coenzyme A domain to function. T8 acetylates the Nα amine group of the amino acid charged to tRNA molecules. This results in N-blocked translationally incompetent aatRNA leading to inhibition of protein synthesis and growth arrest. T8 is a novel acetyltransferase that dimerizes allowing for positive patches on the surface of the dimer to facilitate tRNA binding. Peptidyl tRNA hydrolase (Pth), recognises and hydrolyses T8-acetylated aatRNAs, allowing for the detoxification of cells producing T8 and thereby resumption of growth marking exit from a persister state.
Supervisor: Helaine, Sophie ; Holden, David Sponsor: Imperial College London ; Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral