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Slow Protein Fluctuations Explain the Emergence of Growth Phenotypes and Persistence in Clonal Bacterial Populations

Rocco, A, Kierzek, AM and McFadden, J (2013) Slow Protein Fluctuations Explain the Emergence of Growth Phenotypes and Persistence in Clonal Bacterial Populations PLoS One, 8 (1), e54272.

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Abstract

One of the most challenging problems in microbiology is to understand how a small fraction of microbes that resists killing by antibiotics can emerge in a population of genetically identical cells, the phenomenon known as persistence or drug tolerance. Its characteristic signature is the biphasic kill curve, whereby microbes exposed to a bactericidal agent are initially killed very rapidly but then much more slowly. Here we relate this problem to the more general problem of understanding the emergence of distinct growth phenotypes in clonal populations. We address the problem mathematically by adopting the framework of the phenomenon of so-called weak ergodicity breaking, well known in dynamical physical systems, which we extend to the biological context. We show analytically and by direct stochastic simulations that distinct growth phenotypes can emerge as a consequence of slow-down of stochastic fluctuations in the expression of a gene controlling growth rate. In the regime of fast gene transcription, the system is ergodic, the growth rate distribution is unimodal, and accounts for one phenotype only. In contrast, at slow transcription and fast translation, weakly non-ergodic components emerge, the population distribution of growth rates becomes bimodal, and two distinct growth phenotypes are identified. When coupled to the well-established growth rate dependence of antibiotic killing, this model describes the observed fast and slow killing phases, and reproduces much of the phenomenology of bacterial persistence. The model has major implications for efforts to develop control strategies for persistent infections.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine > Department of Microbial and Cellular Sciences
Authors :
AuthorsEmailORCID
Rocco, AUNSPECIFIEDUNSPECIFIED
Kierzek, AMUNSPECIFIEDUNSPECIFIED
McFadden, JUNSPECIFIEDUNSPECIFIED
Date : 29 January 2013
Identification Number : 10.1371/journal.pone.0054272
Depositing User : Symplectic Elements
Date Deposited : 04 Feb 2013 11:56
Last Modified : 23 Sep 2013 19:59
URI: http://epubs.surrey.ac.uk/id/eprint/749321

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