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Inhibition of stationary phase respiration impairs persister formation in E. coli.

ABSTRACT: Bacterial persisters are rare phenotypic variants that temporarily tolerate high antibiotic concentrations. Persisters have been hypothesized to underlie the recalcitrance of biofilm infections, and strategies to eliminate these cells have the potential to improve treatment outcomes for many hospital-treated infections. Here we investigate the role of stationary phase metabolism in generation of type I persisters in Escherichia coli, which are those that are formed by passage through stationary phase. We find that persisters are unlikely to derive from bacteria with low redox activity, and that inhibition of respiration during stationary phase reduces persister levels by up to ∼1,000-fold. Loss of stationary phase respiratory activity prevents digestion of endogenous proteins and RNA, which yields bacteria that are more capable of translation, replication and concomitantly cell death when exposed to antibiotics. These findings establish bacterial respiration as a prime target for reducing the number of persisters formed in nutrient-depleted, non-growing populations.

SUBMITTER: Orman MA

PROVIDER: S-EPMC4530465 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:To cope with fluctuations in their environment, bacteria have evolved multiple adaptive stress responses. One such response is the nitrogen regulation stress response, which allows bacteria, such as Escherichia coli, to cope with and overcome conditions of nitrogen limitation. This response is directed by the two-component system NtrBC, where NtrC acts as the major transcriptional regulator to activate the expression of genes to mount the response. Recently, my colleagues and I showed that NtrC directly regulates the expression of the relA gene, the major (p)ppGpp synthetase in E. coli, coupling the nitrogen regulation stress and stringent responses. As elevated levels of (p)ppGpp have been implicated in the formation of persister cells, here, I investigated whether nitrogen starvation promotes their formation and whether the NtrC-RelA regulatory cascade plays a role. The results reveal that nitrogen-starved E. coli synthesizes (p)ppGpp and forms a higher percentage of persister cells than nonstarved cells and that both NtrC and RelA are important for these processes. This study provides novel insights into how the formation of persisters can be promoted in response to a nutritional stress.IMPORTANCE Bacteria often reside in environments where nutrient availability is scarce; therefore, they have evolved adaptive responses to rapidly cope with conditions of feast and famine. Understanding the mechanisms that underpin the regulation of how bacteria cope with this stress is a fundamentally important question in the wider context of understanding the biology of the bacterial cell and bacterial pathogenesis. Two major adaptive mechanisms to cope with starvation are the nitrogen regulation (ntr) stress and stringent responses. Here, I describe how these bacterial stress responses are coordinated under conditions of nitrogen starvation to promote the formation of antibiotic-tolerant persister cells by elevating levels of the secondary messenger (p)ppGpp.

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Inhibition of stationary phase respiration impairs persister formation in E. coli.

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