Metabolic aspects of bacterial persisters

Prax, Marcel; Bertram, Ralph

doi:10.3389/fcimb.2014.00148

Cited by 105 publications

(80 citation statements)

References 67 publications

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“…In this regard, it is also possible that CidB may be involved in persister formation, possibly through modulating cellular processes within a population. Persisters constitute a subpopulation of phenotypic variants that are genetically identical and metabolically slow-growing cells in a clonal bacterial population, largely in response to antibiotics (55)(56)(57). Recently, other stress responses and particularly oxidative stress were also reported to contribute to persister formation in Escherichia coli (58).…”

Section: Discussionmentioning

confidence: 99%

“…T/A modules are reported to play a central role in persister formation and/or the persister state (61)(62)(63). T/A modules are also known to function as "regulatory switches" under adverse conditions, allowing cells to enter a state that confers protection against a severe stressful condition or nutrient limitation, ultimately contributing to programmed cell death as a bacterial survival strategy (57,(64)(65)(66). Given that many genes related to PTS, the major route for internalization of carbohydrates in S. mutans, were differentially and highly regulated in the cidB mutant strain, it is also possible that the Cid/Lrg system fine-tunes cellular physiology during periods of stress to help preserve normal cellular homeostasis (e.g., during periods of "feast or famine" in oral plaque) through the potential T/A modules.…”

Section: Discussionmentioning

confidence: 99%

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Understanding the Streptococcus mutans Cid/Lrg System through CidB Function

Ahn

Rice

2016

Appl Environ Microbiol

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The Streptococcus mutans lrgAB and cidAB operons have been previously described as a potential model system to dissect the complexity of biofilm development and virulence of S. mutans. Herein, we have attempted to further characterize the Cid/Lrg system by focusing on CidB, which has been shown to be critical for the ability of S. mutans to survive and persist in a nonpreferred oxygen-enriched condition. We have found that the expression level of cidB is critical to oxidative stress tolerance of S. mutans, most likely by impacting lrg expression. Intriguingly, the impaired aerobic growth phenotype of the cidB mutant could be restored by the additional loss of either CidA or LrgA. Growth-dependent expression of cid and lrg was demonstrated to be tightly under the control of both CcpA and the VicKR two-component system (TCS), regulators known to play an essential role in controlling major catabolic pathways and cell envelope homeostasis, respectively. RNA sequencing (RNA-Seq) analysis revealed that mutation of cidB resulted in global gene expression changes, comprising major domains of central metabolism and virulence processes, particularly in those involved with oxidative stress resistance. Loss of CidB also significantly changed the expression of genes related to genomic islands (GI) TnSmu1 and TnSmu2, the CRISPR (clustered regularly interspaced short palindromic repeats)-Cas system, and toxin-antitoxin (T/A) modules. Taken together, these data show that CidB impinges on the stress response, as well as the fundamental cellular physiology of S. mutans, and further suggest a potential link between Cid/ Lrg-mediated cellular processes, S. mutans pathogenicity, and possible programmed growth arrest and cell death mechanisms. IMPORTANCEThe ability of Streptococcus mutans to survive a variety of harmful or stressful conditions and to emerge as a numerically significant member of stable oral biofilm communities are essential elements for its persistence and cariogenicity. In this study, the homologous cidAB and lrgAB operons, previously identified as being highly balanced and coordinated during S. mutans aerobic growth, were further characterized through the functional and transcriptomic analysis of CidB. Precise control of CidB levels is shown to impact the expression of lrg, oxidative stress tolerance, major metabolic domains, and the molecular modules linked to cell death and lysis. This study advances our understanding of the Cid/Lrg system as a key player in the integration of complex environmental signals (such as oxidative stress) into the regulatory networks that modulate S. mutans virulence and cell homeostasis. Streptococcus mutans, a significant constituent of cariogenic oral biofilms, is capable of withstanding a variety of stressors encountered in the oral cavity. The ability of this bacterium to efficiently and rapidly adjust to the dynamic oral environment is essential for its pathogenic lifestyle. Oxidative stress is one of the most important environmental variables affecting the pathogenic pot...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Understanding the Streptococcus mutans Cid/Lrg System through CidB Function

Ahn

Rice

2016

Appl Environ Microbiol

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“…Metabolism has been emerging as a key modulator of persistence (5,28). Recent studies have demonstrated that metabolic stresses are important sources of persisters in both planktonic cultures and biofilms (29)(30)(31)(32)(33)(34).…”

Section: Discussionmentioning

confidence: 99%

Impacts of Global Transcriptional Regulators on Persister Metabolism

Mok

Orman

Brynildsen

2015

Antimicrob Agents Chemother

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Bacterial persisters are phenotypic variants with an extraordinary capacity to tolerate antibiotics, and they are hypothesized to be a main cause of chronic and relapsing infections. Recent evidence has suggested that the metabolism of persisters can be targeted to develop therapeutic countermeasures; however, knowledge of persister metabolism remains limited due to difficulties associated with isolating these rare and transient phenotypic variants. By using a technique to measure persister catabolic activity, which is based on the ability of metabolites to enable aminoglycoside (AG) killing of persisters, we investigated the role of seven global transcriptional regulators (ArcA, Cra, cyclic AMP [cAMP] receptor protein [CRP], DksA, FNR, Lrp, and RpoS) on persister metabolism. We found that removal of CRP resulted in a loss of AG potentiation in persisters for all metabolites tested. These results highlight a central role for cAMP/CRP in persister metabolism, as its perturbation can significantly diminish the metabolic capabilities of persisters and effectively eliminate the ability of AGs to eradicate these troublesome bacteria. Bacterial persisters are phenotypic variants that are highly tolerant to antibiotics (1). It is believed that they are a main culprit of the proclivity of biofilm infections to relapse, which imposes a substantial burden on the health care system (2, 3). When a bacterial population is treated with bactericidal antibiotics, biphasic killing is observed, where the death of normal cells is characterized by an initial, rapid killing rate, and the presence of persisters is illuminated by a second regime with a much lower rate of cell death (4, 5). When these survivors are recultured, the resulting population exhibits antibiotic sensitivity identical to that of the original culture, demonstrating that persisters are not antibiotic-resistant mutants but phenotypic variants (1, 5, 6).While persisters largely arise from dormant subpopulations (2,4,7,8), recent studies have demonstrated that they remain metabolically active, with the capacity to catabolize specific carbon sources and generate proton motive force through respiration (9, 10). This metabolic activity, specifically, proton motive force generation, enables aminoglycoside (AG) transport into cells that results in killing of persisters, and several enzymes needed for this process have been identified (9, 10). Knowledge of the enzymes and metabolic pathways present in persisters, as well as how they can be altered, could prove useful for the development of antipersister therapies. A fundamental question in this regard is, what are the cellular components responsible for defining the metabolic network in persisters? Due to the strong dependence of metabolism on transcriptional regulation (11, 12), the goal of this study was to determine the importance of several global transcriptional regulators to persister metabolism. To do this, we measured catabolic activity in persisters from ⌬arcA, ⌬cra, ⌬crp, ⌬dksA, ⌬fnr, ⌬lrp, and ⌬rpoS mutants and...

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“…Usually, these were less than 0.1% of the whole population. Much research has been focused on the exploration of the molecular keys linked to the persister phenomenon (37)(38)(39)(40)(41). Bertram and colleagues recently provided evidence that toxin-antitoxin (TA) systems play a key role in the regulatory network of persisters (42,43).…”

Section: Persister Cells As a Classical Model For Phenotypic Heterogementioning

confidence: 99%

Phenotypic Heterogeneity, a Phenomenon That May Explain Why Quorum Sensing Does Not Always Result in Truly Homogenous Cell Behavior

Grote

Krysciak

Streit

2015

Appl Environ Microbiol

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Phenotypic heterogeneity describes the occurrence of "nonconformist" cells within an isogenic population. The nonconformists show an expression profile partially different from that of the remainder of the population. Phenotypic heterogeneity affects many aspects of the different bacterial lifestyles, and it is assumed that it increases bacterial fitness and the chances for survival of the whole population or smaller subpopulations in unfavorable environments. Well-known examples for phenotypic heterogeneity have been associated with antibiotic resistance and frequently occurring persister cells. Other examples include heterogeneous behavior within biofilms, DNA uptake and bacterial competence, motility (i.e., the synthesis of additional flagella), onset of spore formation, lysis of phages within a small subpopulation, and others. Interestingly, phenotypic heterogeneity was recently also observed with respect to quorum-sensing (QS)-dependent processes, and the expression of autoinducer (AI) synthase genes and other QS-dependent genes was found to be highly heterogeneous at a single-cell level. This phenomenon was observed in several Gram-negative bacteria affiliated with the genera Vibrio, Dinoroseobacter, Pseudomonas, Sinorhizobium, and Mesorhizobium. A similar observation was made for the Gram-positive bacterium Listeria monocytogenes. Since AI molecules have historically been thought to be the keys to homogeneous behavior within isogenic populations, the observation of heterogeneous expression is quite intriguing and adds a new level of complexity to the QS-dependent regulatory networks. All together, the many examples of phenotypic heterogeneity imply that we may have to partially revise the concept of homogeneous and coordinated gene expression in isogenic bacterial populations. Bacteria have evolved multiple strategies to cope with rapid and frequent changes in their environment. These survival strategies may include spore formation, increased production of polysaccharides, biofilm formation or escape from biofilms (i.e., switching from a motile into a sessile form and vice versa), altered motility, change of metabolic capabilities, response to antibiotics, and many more. In general, these switches are initiated by environmental or bacterially produced signals that are perceived by a diverse array of regulators and delegated into the corresponding regulatory networks. This presumably results in altered transcription levels of different genes or operons, which eventually causes a change in the phenotype and a response to the environmental stimulus. Within this context, it is generally assumed that the majority of a population will undergo this switch within a short time period and that the population will show a mostly homogeneous expression profile. During the last decade, it became, however, evident that a certain fraction of cells in an isogenic population behaves differently from the others, even though the environment may not have changed significantly. The term "phenotypic heterogeneity" thereby descr...

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Metabolic aspects of bacterial persisters

Cited by 105 publications

References 67 publications

Understanding the Streptococcus mutans Cid/Lrg System through CidB Function

Understanding the Streptococcus mutans Cid/Lrg System through CidB Function

Impacts of Global Transcriptional Regulators on Persister Metabolism

Phenotypic Heterogeneity, a Phenomenon That May Explain Why Quorum Sensing Does Not Always Result in Truly Homogenous Cell Behavior

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