title: Temporal and intrinsic factors of rifampicin tolerance in mycobacteria.
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.
authors.affiliation: 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;
authors.forename: Kirill
authors.initials: K
authors.lastname: Richardson
authors.affiliation: Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02111;
authors.forename: Owen T
authors.initials: OT
authors.lastname: Bennion
authors.affiliation: Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02111;
authors.forename: Shumin
authors.initials: S
authors.lastname: Tan
authors.affiliation: The Center for Engineering in Medicine, Massachusetts General Hospital, Boston, MA 02114;
authors.forename: Anh N
authors.initials: AN
authors.lastname: Hoang
authors.affiliation: 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.
authors.forename: Murat
authors.initials: M
authors.lastname: Cokol
authors.affiliation: 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.
authors.forename: Bree B
authors.initials: BB
authors.lastname: Aldridge
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000502:physiology*; D020102:Mycobacterium smegmatis / Q000187:drug effects* / Q000254:growth & development; D012293:Rifampin / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D012293:Rifampin
keywords: antibiotic susceptibility; cell biology; mathematical modeling; mycobacteria; single cell