title: Dynamic persistence of antibiotic-stressed mycobacteria.
abstract: Exposure of an isogenic bacterial population to a cidal antibiotic typically fails to eliminate a small fraction of refractory cells. Historically, fractional killing has been attributed to infrequently dividing or nondividing "persisters." Using microfluidic cultures and time-lapse microscopy, we found that Mycobacterium smegmatis persists by dividing in the presence of the drug isoniazid (INH). Although persistence in these studies was characterized by stable numbers of cells, this apparent stability was actually a dynamic state of balanced division and death. Single cells expressed catalase-peroxidase (KatG), which activates INH, in stochastic pulses that were negatively correlated with cell survival. These behaviors may reflect epigenetic effects, because KatG pulsing and death were correlated between sibling cells. Selection of lineages characterized by infrequent KatG pulsing could allow nonresponsive adaptation during prolonged drug exposure.
authors.affiliation: School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Wakamoto
authors.forename: Neeraj
authors.initials: N
authors.lastname: Dhar
authors.forename: Remy
authors.initials: R
authors.lastname: Chait
authors.forename: Katrin
authors.initials: K
authors.lastname: Schneider
authors.forename: François
authors.initials: F
authors.lastname: Signorino-Gelo
authors.forename: Stanislas
authors.initials: S
authors.lastname: Leibler
authors.forename: John D
authors.initials: JD
authors.lastname: McKinney
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D002374:Catalase / Q000096:biosynthesis* / Q000235:genetics; D044127:Epigenesis, Genetic; D015964:Gene Expression Regulation, Bacterial; D007538:Isoniazid / Q000494:pharmacology*; D020102:Mycobacterium smegmatis / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D013312:Stress, Physiological
chemical_list: D000995:Antitubercular Agents; D002374:Catalase; D007538:Isoniazid