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Title: Persister formation in Staphylococcus aureus is associated with ATP depletion

Abstract

Persisters are dormant phenotypic variants of bacterial cells that are tolerant to killing by antibiotics1. Persisters are associated with chronic bacterial infection and antibiotic treatment failure. In Escherichia coli, toxin/antitoxin (TA) modules are responsible for persister formation. The mechanism of persister formation in Gram positive bacteria is unknown. Staphylococcus aureus is a major human pathogen, responsible for a variety of chronic and relapsing infections such as osteomyelitis, endocarditis and infections of implanted devices. Deleting TA modules in S. aureus did not affect the level of persisters. Here we show that S. aureus persisters are produced due to a stochastic entrance to stationary phase accompanied by a drop in intracellular ATP. Cells expressing stationary state markers are present throughout the growth phase, increasing in frequency with cell density. Cell sorting revealed that expression of stationary markers was associated with a 100-1000 fold increased likelihood of survival to antibiotic challenge. We find that the antibiotic tolerance of these cells is due to a drop in intracellular ATP. The ATP level of the cell is predictive of bactericidal antibiotic efficacy and explains bacterial tolerance to antibiotic treatment.

Authors:
ORCiD logo; ; ; ; ORCiD logo; ; ; ORCiD logo; ;
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1333435
Report Number(s):
PNNL-SA-116412
Journal ID: ISSN 2058-5276; 453040220
DOE Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article
Journal Name:
Nature Microbiology
Additional Journal Information:
Journal Volume: 1; Journal Issue: 5; Journal ID: ISSN 2058-5276
Country of Publication:
United States
Language:
English

Citation Formats

Conlon, Brian P., Rowe, Sarah E., Gandt, Autumn Brown, Nuxoll, Austin S., Donegan, Niles P., Zalis, Eliza A., Clair, Geremy, Adkins, Joshua N., Cheung, Ambrose L., and Lewis, Kim. Persister formation in Staphylococcus aureus is associated with ATP depletion. United States: N. p., 2016. Web. doi:10.1038/nmicrobiol.2016.51.
Conlon, Brian P., Rowe, Sarah E., Gandt, Autumn Brown, Nuxoll, Austin S., Donegan, Niles P., Zalis, Eliza A., Clair, Geremy, Adkins, Joshua N., Cheung, Ambrose L., & Lewis, Kim. Persister formation in Staphylococcus aureus is associated with ATP depletion. United States. https://doi.org/10.1038/nmicrobiol.2016.51
Conlon, Brian P., Rowe, Sarah E., Gandt, Autumn Brown, Nuxoll, Austin S., Donegan, Niles P., Zalis, Eliza A., Clair, Geremy, Adkins, Joshua N., Cheung, Ambrose L., and Lewis, Kim. 2016. "Persister formation in Staphylococcus aureus is associated with ATP depletion". United States. https://doi.org/10.1038/nmicrobiol.2016.51.
@article{osti_1333435,
title = {Persister formation in Staphylococcus aureus is associated with ATP depletion},
author = {Conlon, Brian P. and Rowe, Sarah E. and Gandt, Autumn Brown and Nuxoll, Austin S. and Donegan, Niles P. and Zalis, Eliza A. and Clair, Geremy and Adkins, Joshua N. and Cheung, Ambrose L. and Lewis, Kim},
abstractNote = {Persisters are dormant phenotypic variants of bacterial cells that are tolerant to killing by antibiotics1. Persisters are associated with chronic bacterial infection and antibiotic treatment failure. In Escherichia coli, toxin/antitoxin (TA) modules are responsible for persister formation. The mechanism of persister formation in Gram positive bacteria is unknown. Staphylococcus aureus is a major human pathogen, responsible for a variety of chronic and relapsing infections such as osteomyelitis, endocarditis and infections of implanted devices. Deleting TA modules in S. aureus did not affect the level of persisters. Here we show that S. aureus persisters are produced due to a stochastic entrance to stationary phase accompanied by a drop in intracellular ATP. Cells expressing stationary state markers are present throughout the growth phase, increasing in frequency with cell density. Cell sorting revealed that expression of stationary markers was associated with a 100-1000 fold increased likelihood of survival to antibiotic challenge. We find that the antibiotic tolerance of these cells is due to a drop in intracellular ATP. The ATP level of the cell is predictive of bactericidal antibiotic efficacy and explains bacterial tolerance to antibiotic treatment.},
doi = {10.1038/nmicrobiol.2016.51},
url = {https://www.osti.gov/biblio/1333435}, journal = {Nature Microbiology},
issn = {2058-5276},
number = 5,
volume = 1,
place = {United States},
year = {Mon Apr 18 00:00:00 EDT 2016},
month = {Mon Apr 18 00:00:00 EDT 2016}
}