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      Definitions and guidelines for research on antibiotic persistence

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          Abstract

          Increasing concerns about the rising rates of antibiotic therapy failure and advances in single-cell analyses have inspired a surge of research into antibiotic persistence. Bacterial persister cells represent a subpopulation of cells that can survive intensive antibiotic treatment without being resistant. Several approaches have emerged to define and measure persistence, and it is now time to agree on the basic definition of persistence and its relation to the other mechanisms by which bacteria survive exposure to bactericidal antibiotic treatments, such as antibiotic resistance, heteroresistance or tolerance. In this Consensus Statement, we provide definitions of persistence phenomena, distinguish between triggered and spontaneous persistence and provide a guide to measuring persistence. Antibiotic persistence is not only an interesting example of non-genetic single-cell heterogeneity, it may also have a role in the failure of antibiotic treatments. Therefore, it is our hope that the guidelines outlined in this article will pave the way for better characterization of antibiotic persistence and for understanding its relevance to clinical outcomes.

          Abstract

          Antibiotic persistence contributes to the survival of bacteria during antibiotic treatment. In this Consensus Statement, scientists working on the response of bacteria to antibiotics define antibiotic persistence and provide practical guidance on how to study bacterial persisters.

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          Most cited references43

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          Bacterial persistence as a phenotypic switch.

          A fraction of a genetically homogeneous microbial population may survive exposure to stress such as antibiotic treatment. Unlike resistant mutants, cells regrown from such persistent bacteria remain sensitive to the antibiotic. We investigated the persistence of single cells of Escherichia coli with the use of microfluidic devices. Persistence was linked to preexisting heterogeneity in bacterial populations because phenotypic switching occurred between normally growing cells and persister cells having reduced growth rates. Quantitative measurements led to a simple mathematical description of the persistence switch. Inherent heterogeneity of bacterial populations may be important in adaptation to fluctuating environments and in the persistence of bacterial infections.
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            Persister cells, dormancy and infectious disease.

            Kim Lewis (2007)
            Several well-recognized puzzles in microbiology have remained unsolved for decades. These include latent bacterial infections, unculturable microorganisms, persister cells and biofilm multidrug tolerance. Accumulating evidence suggests that these seemingly disparate phenomena result from the ability of bacteria to enter into a dormant (non-dividing) state. The molecular mechanisms that underlie the formation of dormant persister cells are now being unravelled and are the focus of this Review.
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              A functional perspective on phenotypic heterogeneity in microorganisms.

              Most microbial communities consist of a genetically diverse assembly of different organisms, and the level of genetic diversity plays an important part in community properties and functions. However, biological diversity also arises at a lower level of biological organization, between genetically identical cells that reside in the same microenvironment. In this Review, I outline the molecular mechanisms responsible for phenotypic heterogeneity and discuss how phenotypic heterogeneity allows genotypes to persist in fluctuating environments. I also describe how it promotes interactions between phenotypic subpopulations in clonal groups, providing microbial groups with new functionality.
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                Author and article information

                Contributors
                nathalie.balaban@mail.huji.ac.il
                Journal
                Nat Rev Microbiol
                Nat. Rev. Microbiol
                Nature Reviews. Microbiology
                Nature Publishing Group UK (London )
                1740-1526
                1740-1534
                12 April 2019
                12 April 2019
                2019
                : 17
                : 7
                : 441-448
                Affiliations
                [1 ]ISNI 0000 0004 1937 0538, GRID grid.9619.7, Racah Institute of Physics, , The Hebrew University, ; Jerusalem, Israel
                [2 ]ISNI 0000 0001 2113 8111, GRID grid.7445.2, MRC Centre for Molecular Bacteriology and Infection, Imperial College London, ; London, UK
                [3 ]ISNI 0000 0001 2173 3359, GRID grid.261112.7, Department of Biology, , Northeastern University, ; Boston, MA USA
                [4 ]ISNI 0000 0001 2156 2780, GRID grid.5801.c, Institute of Biogeochemistry and Pollutant Dynamics, ETH Zurich, ; Zurich, Switzerland
                [5 ]ISNI 0000 0001 1551 0562, GRID grid.418656.8, Department of Environmental Microbiology, Eawag, ; Dubendorf, Switzerland
                [6 ]ISNI 0000 0000 8934 4045, GRID grid.67033.31, Department of Molecular Biology and Microbiology, , Tufts University School of Medicine, ; Boston, MA USA
                [7 ]ISNI 0000 0004 1936 9457, GRID grid.8993.b, Department of Medical Biochemistry and Microbiology, , Uppsala University, ; Uppsala, Sweden
                [8 ]ISNI 0000 0001 2097 5006, GRID grid.16750.35, Department of Chemical and Biological Engineering, , Princeton University, ; Princeton, NJ USA
                [9 ]ISNI 0000 0004 1937 0642, GRID grid.6612.3, Focal Area Infection Biology, , Biozentrum of the University of Basel, ; Basel, Switzerland
                [10 ]ISNI 0000 0001 2341 2786, GRID grid.116068.8, Institute for Medical Engineering & Science, Department of Biological Engineering, and Synthetic Biology Center, , Massachusetts Institute of Technology, ; Cambridge, MA USA
                [11 ]ISNI 000000041936754X, GRID grid.38142.3c, Wyss Institute for Biologically Inspired Engineering, , Harvard University, ; Boston, MA USA
                [12 ]GRID grid.66859.34, Broad Institute of MIT and Harvard, ; Cambridge, MA USA
                [13 ]ISNI 000000041936754X, GRID grid.38142.3c, Department of Immunology and Infectious Diseases, , Harvard T. H. Chan School of Public Health, ; Boston, MA USA
                [14 ]ISNI 0000 0001 2353 6535, GRID grid.428999.7, Institut Pasteur, Genetics of Biofilms Laboratory, ; Paris, France
                [15 ]ISNI 0000 0001 2156 2780, GRID grid.5801.c, Institute of Microbiology, ETH Zurich, ; Zurich, Switzerland
                [16 ]ISNI 0000 0004 0407 1981, GRID grid.4830.f, Molecular Systems Biology, Groningen Biomolecular Sciences and Biotechnology Institute, , University of Groningen, ; Groningen, Netherlands
                [17 ]ISNI 0000 0001 0941 6502, GRID grid.189967.8, Department of Biology, , Emory University, ; Atlanta, GA USA
                [18 ]ISNI 0000 0001 0668 7884, GRID grid.5596.f, Center for Microbiology, , KU Leuven–University of Leuven, ; Leuven, Belgium
                [19 ]ISNI 0000 0000 9635 8082, GRID grid.420089.7, Division of Molecular and Cellular Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, ; Bethesda, MD USA
                [20 ]ISNI 0000 0004 0534 4718, GRID grid.418158.1, Infectious Diseases Department, Genentech, ; South San Francisco, CA USA
                [21 ]ISNI 0000 0001 0943 7661, GRID grid.10939.32, Institute of Technology, , University of Tartu, ; Tartu, Estonia
                [22 ]ISNI 0000 0001 2348 0746, GRID grid.4989.c, Faculté des Sciences, , Université Libre de Bruxelles, ; Bruxelles, Belgium
                [23 ]Division of Infectious Diseases, University Hospital Zurich, University of Zurich, Zurich, Switzerland
                Author information
                http://orcid.org/0000-0001-8018-0766
                http://orcid.org/0000-0002-9877-4180
                http://orcid.org/0000-0001-6640-2174
                http://orcid.org/0000-0002-5560-8246
                http://orcid.org/0000-0001-7565-9975
                http://orcid.org/0000-0002-5512-9077
                Article
                196
                10.1038/s41579-019-0196-3
                7136161
                30980069
                4b9b2386-f89a-436a-82f3-1465af764c7c
                © Springer Nature Limited 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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                Categories
                Consensus Statement
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                © Springer Nature Limited 2019

                antibiotics,bacterial physiology,antimicrobial resistance,antibacterial drug resistance

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