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Proc Natl Acad Sci U S A. 2016 Jul 19;113(29):8302-7. doi: 10.1073/pnas.1600372113. Epub 2016 Jun 29.

Temporal and intrinsic factors of rifampicin tolerance in mycobacteria.

Author information

1
Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02111; Department of Biomedical Engineering, Tufts University School of Engineering, Medford, MA 02155;
2
Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02111;
3
The Center for Engineering in Medicine, Massachusetts General Hospital, Boston, MA 02114;
4
Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02111; Molecular Biology, Genetics and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabancı University, 34956 Istanbul, Turkey; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115.
5
Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02111; Department of Biomedical Engineering, Tufts University School of Engineering, Medford, MA 02155; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115 bree.aldridge@tufts.edu.

Abstract

Mycobacteria grow and divide asymmetrically, creating variability in growth pole age, growth properties, and antibiotic susceptibilities. Here, we investigate the importance of growth pole age and other growth properties in determining the spectrum of responses of Mycobacterium smegmatis to challenge with rifampicin. We used a combination of live-cell microscopy and modeling to prospectively identify subpopulations with altered rifampicin susceptibility. We found two subpopulations that had increased susceptibility. At the initiation of treatment, susceptible cells were either small and at early stages of the cell cycle, or large and in later stages of their cell cycle. In contrast to this temporal window of susceptibility, tolerance was associated with factors inherited at division: long birth length and mature growth poles. Thus, rifampicin response is complex and due to a combination of differences established from both asymmetric division and the timing of treatment relative to cell birth.

KEYWORDS:

antibiotic susceptibility; cell biology; mathematical modeling; mycobacteria; single cell

PMID:
27357669
PMCID:
PMC4961206
DOI:
10.1073/pnas.1600372113
[Indexed for MEDLINE]
Free PMC Article

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