Signaling-mediated bacterial persister formation.
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ABSTRACT:
SUBMITTER: Vega NM
PROVIDER: S-EPMC3329571 | biostudies-literature | 2012 Mar
REPOSITORIES: biostudies-literature
Publications
Signaling-mediated bacterial persister formation.
Vega Nicole M NM Allison Kyle R KR Khalil Ahmad S AS Collins James J JJ
Nature chemical biology 20120318 5
Here we show that bacterial communication through indole signaling induces persistence, a phenomenon in which a subset of an isogenic bacterial population tolerates antibiotic treatment. We monitor indole-induced persister formation using microfluidics and identify the role of oxidative-stress and phage-shock pathways in this phenomenon. We propose a model in which indole signaling 'inoculates' a bacterial subpopulation against antibiotics by activating stress responses, leading to persister for ...[more]
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Project description:Persisters represent a small subpopulation of cells within a bacterial culture that are tolerant to killing by antibiotics. Persisters have been linked to recalcitrant infections caused by numerous bacterial pathogens, including Pseudomonas aeruginosa A classic example is the incurable infection of the airways for patients with cystic fibrosis. The genetic mediators of persister formation for P. aeruginosa are poorly understood. We generated a high-density transposon insertion library of P. aeruginosa PAO1 and determined the relative frequency of each insertion following fluoroquinolone treatment using transposon sequencing (Tn-seq). Of the 4,411 disrupted genes included in the screen, 137 had a ≥10-fold impact on survival. The gene disruption that resulted in the lowest survival rate was disruption of carB, which codes for the large subunit of carbamoyl phosphate synthetase (CPSase). CPSase is a metabolic enzyme that is involved in pyrimidine and arginine synthesis. Disruption of carB resulted in survival rates that were reduced by up to 2,500-fold following antibiotic treatment, and this phenotype was abolished by the addition of uracil, highlighting the importance of de novo pyrimidine biosynthesis for persister formation. Disruption of carB resulted in intracellular ATP accumulation, and lowering ATP levels using arsenate restored the antibiotic tolerance profile of the mutant to levels similar to those seen with the wild type. A decrease in ATP would lead to reduced antibiotic target activity and increased survival.IMPORTANCE Antibiotic treatment of P. aeruginosa residing in the lung of cystic fibrosis patients is ineffective. Treatment failure is attributed in part to antibiotic-tolerant phenotypic variants known as persister cells. Understanding how these cells emerge will likely inform future therapeutic strategies. In the current study, we identified carB, which codes for the large subunit of carbamoyl-phosphate synthetase, as a persister gene that contributes to multidrug tolerance in P. aeruginosa Disruption of carB resulted in a metabolic perturbation that increased cellular ATP and reduced persister formation. Conversely, lowering ATP in the mutant restored antibiotic tolerance. Our data support the hypothesis that a drop in intracellular ATP is a general mechanism of persister formation in bacteria.
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Project description:Bacterial persisters are phenotypic variants that tolerate exposure to lethal antibiotics. These dormant cells are responsible for chronic and recurrent infections. Multiple mechanisms have been linked to persister formation. Here, we report that a complex, consisting of an extracellular poly(dC) and its membrane-associated binding protein RmlB, appears to be associated with persistence of the opportunistic pathogen Pseudomonas aeruginosa. Environmental stimuli triggers a switch in the complex physiological state (from poly(dC)/RmlB to P-poly(dC)/RmlB or RmlB). In response to the switch, bacteria decrease proton motive force and intracellular ATP levels, forming dormant cells. This alteration in complex status is linked to a (p)ppGpp-controlled signaling pathway that includes inorganic polyphosphate, Lon protease, exonuclease VII (XseA/XseB), and the type III secretion system. The persistence might be also an adaptive response to the lethal action of the dTDP-L-rhamnose pathway shutdown, which occurs due to switching of poly(dC)/RmlB.
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Project description:Resistance, tolerance and persistence enable pathogenic bacteria to survive antibiotic treatment and are associated with an elevated risk of treatment failure and relapsing infections. The mechanism underlying bacterial antibiotic persister formation is not well understood. Here, we show that glyoxylate, a metabolite originally evolved to allow bacteria to utilize alternative carbon sources for optimal growth and pathogenicity, also serves as a signaling molecule to alter host gene expression and support persister formation. Specifically, we discovered glyoxylate interacting with TET2 DNA dioxygenase through an in-silico screen of human metabolome. We further show that Salmonella-produced glyoxylate inhibits the activity of Tet2 to suppress the expression of pro-inflammatory genes and attenuate host immune defense. Catalytic inactivation of Tet2, by genetic knock-in mutation, glyoxylate production by Salmonella, or exogenous glyoxylate treatment, facilitates bacterial persister formation in both murine and human macrophages. Conversely, stimulating TET2 with vitamin C or blocking Salmonella production of glyoxylate counters bacterial antibiotic resistance and improves the infection treatment outcomes. In conclusion, our study reveals a novel signaling function of glyoxylate in gene regulation beyond energetic and biosynthetic metabolism. Our findings also suggest that stimulating TET activity within host cells represents a potential therapeutic strategy to combat bacterial persistence.
2025-03-18 | GSE280758 | GEO
Project description:Resistance, tolerance and persistence enable pathogenic bacteria to survive antibiotic treatment and are associated with an elevated risk of treatment failure and relapsing infections. The mechanism underlying bacterial antibiotic persister formation is not well understood. Here, we show that glyoxylate, a metabolite originally evolved to allow bacteria to utilize alternative carbon sources for optimal growth and pathogenicity, also serves as a signaling molecule to alter host gene expression and support persister formation. Specifically, we discovered glyoxylate interacting with TET2 DNA dioxygenase through an in-silico screen of human metabolome. We further show that Salmonella-produced glyoxylate inhibits the activity of Tet2 to suppress the expression of pro-inflammatory genes and attenuate host immune defense. Catalytic inactivation of Tet2, by genetic knock-in mutation, glyoxylate production by Salmonella, or exogenous glyoxylate treatment, facilitates bacterial persister formation in both murine and human macrophages. Conversely, stimulating TET2 with vitamin C or blocking Salmonella production of glyoxylate counters bacterial antibiotic resistance and improves the infection treatment outcomes. In conclusion, our study reveals a novel signaling function of glyoxylate in gene regulation beyond energetic and biosynthetic metabolism. Our findings also suggest that stimulating TET activity within host cells represents a potential therapeutic strategy to combat bacterial persistence.
2025-11-01 | GSE281447 | GEO
Project description:Resistance, tolerance and persistence enable pathogenic bacteria to survive antibiotic treatment and are associated with an elevated risk of treatment failure and relapsing infections. The mechanism underlying bacterial antibiotic persister formation is not well understood. Here, we show that glyoxylate, a metabolite originally evolved to allow bacteria to utilize alternative carbon sources for optimal growth and pathogenicity, also serves as a signaling molecule to alter host gene expression and support persister formation. Specifically, we discovered glyoxylate interacting with TET2 DNA dioxygenase through an in-silico screen of human metabolome. We further show that Salmonella-produced glyoxylate inhibits the activity of Tet2 to suppress the expression of pro-inflammatory genes and attenuate host immune defense. Catalytic inactivation of Tet2, by genetic knock-in mutation, glyoxylate production by Salmonella, or exogenous glyoxylate treatment, facilitates bacterial persister formation in both murine and human macrophages. Conversely, stimulating TET2 with vitamin C or blocking Salmonella production of glyoxylate counters bacterial antibiotic resistance and improves the infection treatment outcomes. In conclusion, our study reveals a novel signaling function of glyoxylate in gene regulation beyond energetic and biosynthetic metabolism. Our findings also suggest that stimulating TET activity within host cells represents a potential therapeutic strategy to combat bacterial persistence.
2025-11-01 | GSE281278 | GEO
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Project description:Toxin-antitoxin (TA) systems are widespread in bacteria and implicated in genome stability, virulence, phage defense and persistence. TA systems have diverse activities and cellular targets, but their physiological roles and regulatory mechanisms are often unclear. Here, we show that the NatR-NatT TA system, which is part of the core genome of the human pathogen Pseudomonas aeruginosa, generates drug-tolerant persisters by specifically depleting nicotinamide dinucleotides. While actively growing P. aeruginosa cells compensate for NatT-mediated NAD+ deficiency by inducing the NAD+ salvage pathway, NAD depletion generates drug tolerant persisters under nutrient-limited conditions. Our structural and biochemical analyses propose a model for NatT toxin activation and autoregulation and indicate that NatT activity is subject to powerful metabolic feedback control by the NAD+ precursor nicotinamide. Based on the identification of natT gain-of-function alleles in patient isolates and on the observation that NatT increases P. aeruginosa virulence, we postulate that NatT modulates pathogen fitness during infections. These findings pave the way for detailed investigations into how a toxin-antitoxin system can promote pathogen persistence by disrupting essential metabolic pathways.
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Project description:Resistance, tolerance and persistence enable pathogenic bacteria to survive antibiotic treatment and are associated with an elevated risk of treatment failure and relapsing infections. The mechanism underlying bacterial antibiotic persister formation is not well understood. Here, we show that glyoxylate, a metabolite originally evolved to allow bacteria to utilize alternative carbon sources for optimal growth and pathogenicity, also serves as a signaling molecule to alter host gene expression and support persister formation. Specifically, we discovered glyoxylate interacting with TET2 DNA dioxygenase through an in-silico screen of human metabolome. We further show that Salmonella-produced glyoxylate inhibits the activity of Tet2 to suppress the expression of pro-inflammatory genes and attenuate host immune defense. Catalytic inactivation of Tet2, by genetic knock-in mutation, glyoxylate production by Salmonella, or exogenous glyoxylate treatment, facilitates bacterial persister formation in both murine and human macrophages. Conversely, stimulating TET2 with vitamin C or blocking Salmonella production of glyoxylate counters bacterial antibiotic resistance and improves the infection treatment outcomes. In conclusion, our study reveals a novel signaling function of glyoxylate in gene regulation beyond energetic and biosynthetic metabolism. Our findings also suggest that stimulating TET activity within host cells represents a potential therapeutic strategy to combat bacterial persistence.
2025-11-01 | GSE281880 | GEO
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