A general model for toxin-antitoxin module dynamics can explain persister cell formation in E. coli

by Gelens, L., Hill, L., Vandervelde, A., Danckaert, J. and Loris, R.
Abstract:
Author Summary Bacterial persistence plays an important role in many chronic infections. Persisters are subpopulations of bacteria which are tolerant to biological stresses such as antibiotics because they are in a dormant, non-dividing state. Toxin-antitoxin (TA) modules play a pivotal role in persister generation and bacterial stress response. These small genetic loci, ubiquitous in bacterial genomes and plasmids, code for a toxin that slows down or halts bacterial metabolism and a corresponding antitoxin that regulates this activity. In order to further unravel the intricate autoregulation of TA modules and their role in persister cell formation, we built stochastic models describing the transcriptional regulation including conditional cooperativity. This is a complex mechanism in which the molar ratio between both proteins determines whether the toxin will behave as a co-repressor or as a de-repressor for the antitoxin. We found that the necessary protein production and therefore the energetic cost decreases with increased binding site number. Finally, these models allow us to simulate the formation of persister cells through rare, stochastic increases in the free toxin level. We believe that our analysis provides a fresh view and contributes to our understanding of TA regulation and how it may be related to the emergence of persisters.
Reference:
A general model for toxin-antitoxin module dynamics can explain persister cell formation in E. coli Gelens, L., Hill, L., Vandervelde, A., Danckaert, J. and Loris, R., PLOS Computational Biology, volume 9, pp. e1003190, 2013.
Bibtex Entry:
@article{gelens_general_2013,
	title = {A {general} {model} for {toxin}-{antitoxin} {module} {dynamics} {can} {explain} {persister} {cell} {formation} in <i>{E}. coli</i>},
	volume = {9},
	issn = {1553-7358},
	url = {http://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1003190},
	doi = {10.1371/journal.pcbi.1003190},
	abstract = {Author Summary  Bacterial persistence plays an important role in many chronic infections. Persisters are subpopulations of bacteria which are tolerant to biological stresses such as antibiotics because they are in a dormant, non-dividing state. Toxin-antitoxin (TA) modules play a pivotal role in persister generation and bacterial stress response. These small genetic loci, ubiquitous in bacterial genomes and plasmids, code for a toxin that slows down or halts bacterial metabolism and a corresponding antitoxin that regulates this activity. In order to further unravel the intricate autoregulation of TA modules and their role in persister cell formation, we built stochastic models describing the transcriptional regulation including conditional cooperativity. This is a complex mechanism in which the molar ratio between both proteins determines whether the toxin will behave as a co-repressor or as a de-repressor for the antitoxin. We found that the necessary protein production and therefore the energetic cost decreases with increased binding site number. Finally, these models allow us to simulate the formation of persister cells through rare, stochastic increases in the free toxin level. We believe that our analysis provides a fresh view and contributes to our understanding of TA regulation and how it may be related to the emergence of persisters.},
	number = {8},
	urldate = {2016-11-07},
	journal = {PLOS Computational Biology},
	author = {Gelens, L. and Hill, L. and Vandervelde, A. and Danckaert, J. and Loris, R.},
	month = aug,
	year = {2013},
	keywords = {Antitoxins, Biochemical simulations, Cell binding, DNA-binding proteins, Gene regulation, Messenger RNA, Toxin-antitoxin modules, Toxins},
	pages = {e1003190},
	file = {Full Text PDF:/home/jan/.zotero/zotero/djuw86a6.default/zotero/storage/QTFVI4GC/Gelens et al. - 2013 - A General Model for Toxin-Antitoxin Module Dynamic.pdf:application/pdf;Snapshot:/home/jan/.zotero/zotero/djuw86a6.default/zotero/storage/HAKZZD7E/article.html:text/html}
}