Bacterial Persisters Are a Stochastically Formed Subpopulation of Low-energy Cells

Overview

Journal PLoS Biol

Specialty Biology

Date 2021 Apr 19

PMID 33872303

Citations 67

Authors

Sylvie Manuse

Yue Shan

Silvia J Canas-Duarte

Somenath Bakshi

Wei-Sheng Sun

Hirotada Mori

Johan Paulsson

Kim Lewis

Affiliations

Soon will be listed here.

Abstract

Persisters represent a small subpopulation of non- or slow-growing bacterial cells that are tolerant to killing by antibiotics. Despite their prominent role in the recalcitrance of chronic infections to antibiotic therapy, the mechanism of their formation has remained elusive. We show that sorted cells of Escherichia coli with low levels of energy-generating enzymes are better able to survive antibiotic killing. Using microfluidics time-lapse microscopy and a fluorescent reporter for in vivo ATP measurements, we find that a subpopulation of cells with a low level of ATP survives killing by ampicillin. We propose that these low ATP cells are formed stochastically as a result of fluctuations in the abundance of energy-generating components. These findings point to a general "low energy" mechanism of persister formation.

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References

Balaban N, Merrin J, Chait R, Kowalik L, Leibler S . Bacterial persistence as a phenotypic switch. Science. 2004; 305(5690):1622-5. DOI: 10.1126/science.1099390. View

Kim J, Chowdhury N, Yamasaki R, Wood T . Viable but non-culturable and persistence describe the same bacterial stress state. Environ Microbiol. 2018; 20(6):2038-2048. DOI: 10.1111/1462-2920.14075. View

Dorr T, Vulic M, Lewis K . Ciprofloxacin causes persister formation by inducing the TisB toxin in Escherichia coli. PLoS Biol. 2010; 8(2):e1000317. PMC: 2826370. DOI: 10.1371/journal.pbio.1000317. View

Windels E, Ben Meriem Z, Zahir T, Verstrepen K, Hersen P, Van den Bergh B . Enrichment of persisters enabled by a ß-lactam-induced filamentation method reveals their stochastic single-cell awakening. Commun Biol. 2019; 2:426. PMC: 6884588. DOI: 10.1038/s42003-019-0672-3. View

Huang C, Gonzalez-Lopez C, Henry C, Mijakovic I, Ryan K . hipBA toxin-antitoxin systems mediate persistence in Caulobacter crescentus. Sci Rep. 2020; 10(1):2865. PMC: 7029023. DOI: 10.1038/s41598-020-59283-x. View

Rowe S, Wagner N, Li L, Beam J, Wilkinson A, Radlinski L . Reactive oxygen species induce antibiotic tolerance during systemic Staphylococcus aureus infection. Nat Microbiol. 2019; 5(2):282-290. PMC: 6992501. DOI: 10.1038/s41564-019-0627-y. View

Tuomanen E, Cozens R, Tosch W, Zak O, Tomasz A . The rate of killing of Escherichia coli by beta-lactam antibiotics is strictly proportional to the rate of bacterial growth. J Gen Microbiol. 1986; 132(5):1297-304. DOI: 10.1099/00221287-132-5-1297. View

Goormaghtigh F, Fraikin N, Putrins M, Hallaert T, Hauryliuk V, Garcia-Pino A . Reassessing the Role of Type II Toxin-Antitoxin Systems in Formation of Escherichia coli Type II Persister Cells. mBio. 2018; 9(3). PMC: 6016239. DOI: 10.1128/mBio.00640-18. View

Conlon B, Nakayasu E, Fleck L, LaFleur M, Isabella V, Coleman K . Activated ClpP kills persisters and eradicates a chronic biofilm infection. Nature. 2013; 503(7476):365-70. PMC: 4031760. DOI: 10.1038/nature12790. View

10.

McKenzie G, Craig N . Fast, easy and efficient: site-specific insertion of transgenes into enterobacterial chromosomes using Tn7 without need for selection of the insertion event. BMC Microbiol. 2006; 6:39. PMC: 1475584. DOI: 10.1186/1471-2180-6-39. View

11.

Lobas M, Tao R, Nagai J, Kronschlager M, Borden P, Marvin J . A genetically encoded single-wavelength sensor for imaging cytosolic and cell surface ATP. Nat Commun. 2019; 10(1):711. PMC: 6372613. DOI: 10.1038/s41467-019-08441-5. View

12.

Joers A, Kaldalu N, Tenson T . The frequency of persisters in Escherichia coli reflects the kinetics of awakening from dormancy. J Bacteriol. 2010; 192(13):3379-84. PMC: 2897658. DOI: 10.1128/JB.00056-10. View

13.

Wang P, Robert L, Pelletier J, Dang W, Taddei F, Wright A . Robust growth of Escherichia coli. Curr Biol. 2010; 20(12):1099-103. PMC: 2902570. DOI: 10.1016/j.cub.2010.04.045. View

14.

Liu J, Gefen O, Ronin I, Bar-Meir M, Balaban N . Effect of tolerance on the evolution of antibiotic resistance under drug combinations. Science. 2020; 367(6474):200-204. DOI: 10.1126/science.aay3041. View

15.

Ronneau S, Helaine S . Clarifying the Link between Toxin-Antitoxin Modules and Bacterial Persistence. J Mol Biol. 2019; 431(18):3462-3471. DOI: 10.1016/j.jmb.2019.03.019. View

16.

Germain E, Castro-Roa D, Zenkin N, Gerdes K . Molecular mechanism of bacterial persistence by HipA. Mol Cell. 2013; 52(2):248-54. DOI: 10.1016/j.molcel.2013.08.045. View

17.

Radzikowski J, Vedelaar S, Siegel D, Ortega A, Schmidt A, Heinemann M . Bacterial persistence is an active σS stress response to metabolic flux limitation. Mol Syst Biol. 2016; 12(9):882. PMC: 5043093. DOI: 10.15252/msb.20166998. View

18.

Yaginuma H, Kawai S, Tabata K, Tomiyama K, Kakizuka A, Komatsuzaki T . Diversity in ATP concentrations in a single bacterial cell population revealed by quantitative single-cell imaging. Sci Rep. 2014; 4:6522. PMC: 4185378. DOI: 10.1038/srep06522. View

19.

Rycroft J, Gollan B, Grabe G, Hall A, Cheverton A, Larrouy-Maumus G . Activity of acetyltransferase toxins involved in Salmonella persister formation during macrophage infection. Nat Commun. 2018; 9(1):1993. PMC: 5959882. DOI: 10.1038/s41467-018-04472-6. View

20.

Amato S, Orman M, Brynildsen M . Metabolic control of persister formation in Escherichia coli. Mol Cell. 2013; 50(4):475-87. DOI: 10.1016/j.molcel.2013.04.002. View