title: Stochastic expression of a multiple antibiotic resistance activator confers transient resistance in single cells.
abstract: Transient resistance can allow microorganisms to temporarily survive lethal concentrations of antibiotics. This can be accomplished through stochastic mechanisms, where individual cells within a population display diverse phenotypes to hedge against the appearance of an antibiotic. To date, research on transient stochastic resistance has focused primarily on mechanisms where a subpopulation of cells enters a dormant, drug-tolerant state. However, a fundamental question is whether stochastic gene expression can also generate variable resistance levels among growing cells in a population. We hypothesized that stochastic expression of antibiotic-inducible resistance mechanisms might play such a role. To investigate this, we focused on a prototypical example of such a system: the multiple antibiotic resistance activator MarA. Previous studies have shown that induction of MarA can lead to a multidrug resistant phenotype at the population level. We asked whether MarA expression also has a stochastic component, even when uninduced. Time lapse microscopy showed that isogenic cells express heterogeneous, dynamic levels of MarA, which were correlated with transient antibiotic survival. This finding has important clinical implications, as stochastic expression of resistance genes may be widespread, allowing populations to hedge against the sudden appearance of an antibiotic.
authors.affiliation: School of Engineering, University of Vermont, Burlington, VT USA 05405.
authors.forename: Imane
authors.initials: I
authors.lastname: El Meouche
authors.affiliation: School of Engineering, University of Vermont, Burlington, VT USA 05405.
authors.forename: Yik
authors.initials: Y
authors.lastname: Siu
authors.affiliation: School of Engineering, University of Vermont, Burlington, VT USA 05405.
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Dunlop
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002228:Carbenicillin / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics*; D024901:Drug Resistance, Multiple, Bacterial; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics* / Q000254:growth & development; D029968:Escherichia coli Proteins / Q000235:genetics*; D015870:Gene Expression; D015964:Gene Expression Regulation, Bacterial; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; C080002:MarA protein, E coli; D002228:Carbenicillin