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Research Article

Robust, linear correlations between growth rates and β-lactam–mediated lysis rates

Anna J. Lee, Shangying Wang, Hannah R. Meredith, Bihan Zhuang, Zhuojun Dai, and Lingchong You
  1. aDepartment of Biomedical Engineering, Duke University, Durham, NC 27708;
  2. bCenter for Genomic and Computational Biology, Duke University, Durham, NC 27708;
  3. cDepartment of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710

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PNAS April 17, 2018 115 (16) 4069-4074; first published April 2, 2018; https://doi.org/10.1073/pnas.1719504115
Anna J. Lee
aDepartment of Biomedical Engineering, Duke University, Durham, NC 27708;
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Shangying Wang
aDepartment of Biomedical Engineering, Duke University, Durham, NC 27708;
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Hannah R. Meredith
aDepartment of Biomedical Engineering, Duke University, Durham, NC 27708;
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Bihan Zhuang
aDepartment of Biomedical Engineering, Duke University, Durham, NC 27708;
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Zhuojun Dai
aDepartment of Biomedical Engineering, Duke University, Durham, NC 27708;
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Lingchong You
aDepartment of Biomedical Engineering, Duke University, Durham, NC 27708;
bCenter for Genomic and Computational Biology, Duke University, Durham, NC 27708;
cDepartment of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710
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  • For correspondence: you@duke.edu
  1. Edited by Ken A. Dill, Stony Brook University, Stony Brook, NY, and approved March 7, 2018 (received for review November 8, 2017)

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Significance

How fast bacteria grow influences the efficacy of β-lactams, one of the most commonly used classes of antibiotics. However, the quantitative nature of this correlation is not well established. With precise measurements and analyses enabled by experimental automation, we found a robust relationship between growth and lysis rates that is generally applicable to diverse pairs of β-lactams and bacteria. That is, the growth rate of population serves as a reliable predictor for the lysis rate in response to a β-lactam. This quantitative correlation lays the foundation for predicting bacterial population dynamics during β-lactam treatments. This predictive capability is critical for designing effective antibiotic dosing protocols, in addressing the rising antibiotic resistance crisis.

Abstract

It is widely acknowledged that faster-growing bacteria are killed faster by β-lactam antibiotics. This notion serves as the foundation for the concept of bacterial persistence: dormant bacterial cells that do not grow are phenotypically tolerant against β-lactam treatment. Such correlation has often been invoked in the mathematical modeling of bacterial responses to antibiotics. Due to the lack of thorough quantification, however, it is unclear whether and to what extent the bacterial growth rate can predict the lysis rate upon β-lactam treatment under diverse conditions. Enabled by experimental automation, here we measured >1,000 growth/killing curves for eight combinations of antibiotics and bacterial species and strains, including clinical isolates of bacterial pathogens. We found that the lysis rate of a bacterial population linearly depends on the instantaneous growth rate of the population, regardless of how the latter is modulated. We further demonstrate that this predictive power at the population level can be explained by accounting for bacterial responses to the antibiotic treatment by single cells. This linear dependence of the lysis rate on the growth rate represents a dynamic signature associated with each bacterium–antibiotic pair and serves as the quantitative foundation for designing combination antibiotic therapy and predicting the population-structure change in a population with mixed phenotypes.

  • beta-lactams
  • systems biology
  • quantitative biology
  • antibiotic resistance

Footnotes

  • ↵1To whom correspondence should be addressed. Email: you{at}duke.edu.
  • Author contributions: A.J.L. and L.Y. designed research; A.J.L., S.W., H.R.M., B.Z., and Z.D. performed research; A.J.L., S.W., H.R.M., and L.Y. contributed new reagents/analytic tools; A.J.L., S.W., and L.Y. analyzed data; and A.J.L., S.W., and L.Y. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1719504115/-/DCSupplemental.

Published under the PNAS license.

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Robust, linear correlations between growth rates and β-lactam–mediated lysis rates
Anna J. Lee, Shangying Wang, Hannah R. Meredith, Bihan Zhuang, Zhuojun Dai, Lingchong You
Proceedings of the National Academy of Sciences Apr 2018, 115 (16) 4069-4074; DOI: 10.1073/pnas.1719504115

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Robust, linear correlations between growth rates and β-lactam–mediated lysis rates
Anna J. Lee, Shangying Wang, Hannah R. Meredith, Bihan Zhuang, Zhuojun Dai, Lingchong You
Proceedings of the National Academy of Sciences Apr 2018, 115 (16) 4069-4074; DOI: 10.1073/pnas.1719504115
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Proceedings of the National Academy of Sciences: 115 (16)
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