Persisters: Bacterial Cells That Ignore Antibiotics

Abstracts & Commentary

Synopsis: Exposure of E. coli to ampicillin results in selection of a preexisting population of persister cells. Persistence may also be induced by ampicillin exposure via activation of the SOS response.

Sources: Miller C, et al. SOS Response Induction By B-Lactams and Bacterial Defense Against Antibiotic lethality. Science. 2004;305:1629-1631.; Balaban NQ, et al. Bacterial Persistence as a Phenotypic Switch. Science. 2004;305: 1622-1625.

Balaban and colleagues developed microfluidic devices that allowed observation of the growth of individual bacteria. Mutant (hip-for high persisters) E. coli with a high proportion of persisting cells when exposted to antibiotics were utilized.

Examination of individual hip E. coli demonstrated that the persisters, distinguished by their reduced growth rate, were present even in the absence of antibiotic exposure. Exposure of the organism to ampicillin, to which it was susceptible, led to rapid initial killing, followed by a slower phase and the persistence of a small number of viable bacteria that remained susceptible to the antibiotic. These organisms, capable of persisting despite antibiotic exposure, arose from individual bacterial cells that had the slow growth characteristics of persisters observed in the absence of antibiotic pressure. Some persister cells were able to spontaneously switch from an apparently arrested growth state to fast growth, generating a population that remained antibiotic susceptible.

Miller and colleagues found that exposure of susceptible E. coli to ampicillin, and the consequent inactivation of PBP3, results in activation of the DpiBA 2 component signal transduction system. This subsequently triggers the SOS DNA repair response, resulting in the cessation of cell division and cell wall synthesis, allowing the bacterial cell to survive in the presence of the antibiotic, which requires the presence of bacterial replication for its lethal effect.

Comment by Stan Deresinski, MD, FACP

In the context of antimicrobial therapy, bacterial persistence is the phenomenon in which a small proportion of a microbial population survives exposure to an antibiotic, despite the absence of true resistance to the drug. The latter is demonstrated by reexposing an expanded population of the persisters to the same antibiotic with, once again, rapid killing of the majority of the population, but persistence of a small portion of the population. Bacterial persisters have been called specialized survivor cells.1

Balaban and colleagues demonstrate that these persisters, characterized by slowed growth, are present even in the absence of an antibiotic. Antibiotic exposure, rather than inducing the persister phenotype, simply selects preexisting persisters from among a larger population rapidly killed by the antibiotic.

Miller and colleagues found that inactivation of the transpeptidase PBP3 activates a 2 component signaling system, ultimately leading to activation of the SOS response. The SOS response is a DNA damage repair and cell cycle control system, and its activation results in blockade of the cell cycle, global mutagenesis, and upregulation of DNA repair and recombination. All of these effects attempt to assure cell survival (persistence) in the presence of an otherwise lethal stressor.

These 2 papers describe 2 apparently distinct aspects of bacterial persistence—the presence of preexisting cells with this phenotype that are selected by antibiotic exposure, and the creation of persisters by activation of the SOS response as a consequence of inactivation of PBP2 by ampicillin. With regard to the latter observation, it would be of interest to determine if a beta-lactam antibiotic such as imipenem, that is relatively selective for E. coli PBP3, rather than PBP2, would have the same effect on the SOS response.

Finally, there is at least 1 possible connection between the phenotypic antibiotic resistance represented by persisters and classical antibiotic resistance, since it has been demonstrated that SOS activation promotes horizontal transfer of antibiotic resistance genes.2

References

1. Keren I, et al. Persister Cells and Tolerance to Antimicrobials. FEMS. Microbiol Lett. 2004;230:13-18.

2. Beaber JW, et al. SOS Response Promotes Horizontal Dissemination of Antibiotic Resistance Genes. Nature. 2004;427:72-74.

Stan Deresinski, MD, FACP, Clinical Professor of Medicine, Stanford; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, is Editor for Infectious Disease Alert.