Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 29, Pages 8302-8307Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1600372113
Keywords
antibiotic susceptibility; single cell; mathematical modeling; mycobacteria; cell biology
Categories
Funding
- Alfred P. Sloan Foundation Research Fellowship
- NIH Director's New Innovator Award [1DP2LM011952-01]
- Harvard Laboratory of Systems Pharmacology Center [P50GM107618]
- NIH [K99AI114952, 5P41EB002503-12]
- Turkish Academy of Sciences GEBIP Fellowship
- TUBITAK Grant [115S934]
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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.
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