Tolerant, Growing Cells from Nutrient Shifts Are Not Persister Cells

Abstract

There is much controversy about the metabolic state of cells that are tolerant to antibiotics, known as persister cells. In this opinion piece, we offer an explanation for the discrepancy seen: some laboratories are studying metabolically active and growing cell populations (e.g., as a result of nutrient shifts) and attributing the phenotypes that they discern to persister cells while other labs are studying dormant cells. We argue here that the metabolically active cell population should more accurately be considered tolerant cells, while the dormant cells are the true persister population.

Keywords: antimicrobial agents; persistence; tolerance.

FIG 1

Major mechanisms used by bacteria to survive antibiotics. Resistance is the use of the active defense mechanism of mutation to withstand antibiotic (Ab) stress; surviving cells grow in the presence of the antibiotic, and offspring inherit the phenotype. The mutations include those that inactivate antibiotics by increasing efflux, by target modification, and by direct antibiotic modification. Persistence is the cessation of cellular activity (i.e., dormancy) that allows cells to not grow in the presence of antibiotics but basically to not change in concentration. The persistence phenotype is not inherited, and cells revert rapidly to wild-type growth once the antibiotic stress is removed and nutrients are presented. Tolerance is due to slow growth prior to the antibiotic stress, and the slow-growing cells utilize universal defense mechanisms (e.g., RpoS, superoxide dismutase [SOD], and heat/cold shock proteins) to counter various environmental stresses such as carbon shifts and lack of nutrients. Upon antibiotic addition, the concentration of tolerant cells decreases continually, and the phenotype of tolerance is noninherited.