Critically reviewed the manuscript: MNBM. Both authors read and approved the final manuscript.”
“Background Bacterial persistence is a form of phenotypic heterogeneity in which a subset of cells within an isogenic

population is able to survive challenges with antibiotics or other stressors better than the bulk of the population [1]. The persistence phenotype is transient and non-genetic, in contrast to antibiotic resistance, which is due to genetic changes. However, the ability to form persister cells, or the fraction of persister cells that are present in a culture, can be genetically controlled (see below). KPT-8602 nmr The phenomenon of persistence has significant clinical relevance [2], and it may be a primary factor as to why many infections require long-course antibiotic treatment for successful resolution [3]. Indeed, many patients with chronic infections harbor pathogens with increased rates of persister formation [4]. Thus, one of the most important questions concerning persister formation is determining the mechanisms that allow cells to become physiologically recalcitrant to treatment with antibiotics or other stressors. Recent work has suggested that persisters become drug tolerant because they enter a dormant or slow-growing state [5–9]. This

dormant state is thought to protect them from the lethal action of antimicrobials, since many antibiotics interfere with proliferative processes, such as cell wall assembly, DNA replication, INK1197 or protein synthesis [7, 10]. Genetic studies in E. coli K12 have implicated several genes that play a role in the rate of formation of both dormant and persister cells. Many of these genes Tryptophan synthase encode

toxin-antitoxin (TA) modules [7, 8, 11]. One example is hipA (high persistence). One allele of this gene (hipA7) causes a 100 to 1000-fold increase in persister levels [12], and over-expression of hipA leads to growth arrest and a persistence phenotype [13]. Several other loci have also been associated. Maisonneuve et al. [11] recently showed that overexpression of any one of five toxins from mRNase TA pairs resulted in higher fractions of persisters for both ciprofloxacin and ampicillin. In addition, by serially deleting up to ten TA loci, the authors showed that decreasing the number of TA loci decreased the fraction of persisters. Deleting ten TA loci decreased the persister fraction by 100-fold, from approximately 1% to 0.01% after five hours of antibiotic treatment, and this decrease occurred for both ciprofloxacin and ampicillin. The authors proposed a model in which mRNase toxins inhibit global translation, cells become dormant, and thus persist. These data suggest that in E. coli K12, a substantial fraction of persisters arise through mechanisms involving mRNase TA loci (deleting all ten loci results in a 99% reduction in persister frequency; deleting any one locus results in only an approximately 10% reduction in persister frequency). It is unknown whether similar mechanisms are important in other bacteria.