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 antibiotics(1). Persisters are associated with chronic infections and antibiotic treatment failure(1-3). In Escherichia coli, toxin-antitoxin modules have been linked to persister formation(4-6). 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 toxin-antitoxin 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 into the stationary phase accompanied by a drop in intracellular adenosine triphosphate. Cells expressing stationary-state markers are present throughout the growth phase, and increase in frequency with cell density. Cell sorting revealed that the expression of stationary markers is associated with a 100-1,000-fold increase in the likelihood of survival to antibiotic challenge. The adenosine triphosphate level of the cell is predictive of bactericidal antibiotic efficacy and explains bacterial tolerance to antibiotics.
authors: Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, Massachusetts 02115, USA.
authors: Brian P
authors: http://orcid.org/0000-0002-2155-8375
authors: BP
authors: Conlon
authors: Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, Massachusetts 02115, USA.|Synlogic, Cambridge, Massachusetts 02139, USA.
authors: Sarah E
authors: SE
authors: Rowe
authors: Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, Massachusetts 02115, USA.
authors: Autumn Brown
authors: AB
authors: Gandt
authors: Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, Massachusetts 02115, USA.
authors: Austin S
authors: AS
authors: Nuxoll
authors: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755, USA.
authors: Niles P
authors: http://orcid.org/0000-0002-8328-2044
authors: NP
authors: Donegan
authors: Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, Massachusetts 02115, USA.
authors: Eliza A
authors: EA
authors: Zalis
authors: Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99352, USA.
authors: Geremy
authors: G
authors: Clair
authors: Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99352, USA.
authors: Joshua N
authors: http://orcid.org/0000-0003-0399-0700
authors: JN
authors: Adkins
authors: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755, USA.
authors: Ambrose L
authors: AL
authors: Cheung
authors: Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, Massachusetts 02115, USA.
authors: Kim
authors: K
authors: Lewis
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D004361:Drug Tolerance; D013211:Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D000255:Adenosine Triphosphate