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Bacterial single cell RNA-seq unveils cyclic-di-GMP as an antitoxin critical for antibiotic tolerance in biofilm [scRNA-seq]

ABSTRACT: Biofilms are heterogeneous bacterial communities featured by high persister prevalence, responsible for antibiotic tolerance. However, the mechanisms underlying persister formation within biofilms remained ambiguous. Here, by developing and utilizing a ribosomal RNA depleted bacterial single-cell RNA-seq method, RiboD-mSPLiT, we resolved biofilm heterogeneity and discovered pdeI as a marker gene for persister subgroup within biofilms. Remarkably, our findings elucidated that PdeI upregulates cellular levels of c-di-GMP, which acts as an antitoxin to modulate the toxicity of toxin protein HipH. HipH localizes on nucleoid and functions as a potent DNase, inducing cells into a viable but non-culturable state. Conversely, c-di-GMP interacts with HipH, reducing its genotoxic effects and enabling cells to enter a persister state, resulting in drug tolerance. Importantly, by targeting this toxin-antitoxin system, we repressed drug tolerance in Uropathogenic Escherichia coli infections, offering promising therapeutic strategies against chronic and relapsing infections.

ORGANISM(S): Escherichia coli str. K-12 substr. MG1655 Staphylococcus aureus Pseudomonas aeruginosa PAO1

PROVIDER: GSE239504 | GEO | 2024/02/20

REPOSITORIES: GEO

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Bacterial single cell RNA-seq unveils cyclic-di-GMP as an antitoxin critical for antibiotic tolerance in biofilm [RNA-seq]

Project description:Biofilms are heterogeneous bacterial communities featured by high persister prevalence, responsible for antibiotic tolerance. However, the mechanisms underlying persister formation within biofilms remained ambiguous. Here, by developing and utilizing a ribosomal RNA depleted bacterial single-cell RNA-seq method, RiboD-mSPLiT, we resolved biofilm heterogeneity and discovered pdeI as a marker gene for persister subgroup within biofilms. Remarkably, our findings elucidated that PdeI upregulates cellular levels of c-di-GMP, which acts as an antitoxin to modulate the toxicity of toxin protein HipH. HipH localizes on nucleoid and functions as a potent DNase, inducing cells into a viable but non-culturable state. Conversely, c-di-GMP interacts with HipH, reducing its genotoxic effects and enabling cells to enter a persister state, resulting in drug tolerance. Importantly, by targeting this toxin-antitoxin system, we repressed drug tolerance in Uropathogenic Escherichia coli infections, offering promising therapeutic strategies against chronic and relapsing infections.

2024-02-20 | GSE239503 | GEO

Bacterial single cell RNA-seq unveils cyclic-di-GMP as an antitoxin critical for antibiotic tolerance in biofilm [ChIP-seq]

2024-02-20 | GSE239502 | GEO

Persistence of BW25113 mqsR producing MqsR 2-1 vs. producing wild-type MqsR with ampicillin

Project description:Persisters are a subpopulation of metabolically-dormant cells in biofilms that are resistant to antibiotics; hence, understanding persister cell formation is important for controlling bacterial infections. Previously we discerned that MqsR and MqsA of Escherichia coli are a toxin/antitoxin pair that influence persister cell production via their regulation of Hha, CspD, and HokA. Here, to gain more insights into the origin of persisters, we used protein engineering to increase the toxicity of toxin MqsR by reasoning it would be easier to understand the effect of this toxin if it were more toxic. We found that two mutations (K3N and N31Y) increase the toxicity four fold and increase persistence 73 fold compared to native MqsR by making the protein less labile. A whole transcriptome study revealed that the MqsR variant represses acid resistance genes (gadABCEWX and hdeABD), multidrug resistance genes (mdtEF), and osmotic resistance genes (osmEY). Corroborating these microarray results, deletion of rpoS as well as the genes that the master stress response regulator RpoS controls, gadB, gadX, mdtF, and osmY, increased persister formation dramatically to the extent that nearly the whole population became persistent. Therefore, the more toxic MqsR increases persistence by decreasing the ability of the cell to respond to antibiotic stress through its RpoS-based regulation of acid resistance, multidrug resistance, and osmotic resistance systems.

2012-04-03 | GSE31054 | GEO

Expression profile for overproduction of ArT

Project description:Toxin-antitoxin (TA) systems are ubiquitous throughout bacterial and archaeal genomes. TA systems consist of a stable toxin that inhibits growth and a labile antitoxin that prevents toxicity of the toxin. Here we made an artificial TA system (arT/arA) and performed a DNA microarray study for overproduction of the toxin.

2014-05-13 | GSE54271 | GEO

Expression profile for overproduction of DosP

Project description:Persister cells are a sub-population of all bacterial cultures which exhibit a non-inheritable, multi-drug tolerance when subjected to lethal antibiotic challenge. These persisters arise as a result of metabolic dormancy, and can resume growth subsequent to antibiotic challenge, leading to recalcitrance of bacterial infections. Overproduction of DosP, an oxygen sensing protein with phosphodiesterase activity, increases bacterial persistence. Here we performed a microarray to determine the expression profile induced by DosP as a means to elucidate mechanisms of persister cell formation. dosP was overexpressed in Escherichia coli K-12 BW25113 and compared to the empty vector.

2014-09-15 | E-GEOD-47427 | biostudies-arrayexpress

HipBA toxin-antitoxin system Caulobacter crescentus.

Project description:Antibiotic persistence is a transient phenotypic state during which a bacterium can withstand otherwise lethal antibiotic exposure or environmental stresses. In Escherichia coli, persistence is promoted by the HipBA toxin-antitoxin system. The HipA toxin functions as a serine/threonine kinase that inhibits cell growth, while the HipB antitoxin neutralizes the toxin. E. coli HipA inactivates the glutamyl-tRNA synthetase GltX, which inhibits translation and triggers the highly conserved stringent response. Although hipBA operons are widespread in bacterial genomes, it is unknown if this mechanism is conserved in other species. Here we describe the functions of three hipBA modules in the alpha-proteobacterium Caulobacter crescentus. The HipA toxins have different effects on growth and macromolecular syntheses, and they phosphorylate distinct substrates. HipA1 and HipA2 contribute to antibiotic persistence during stationary phase by phosphorylating the aminoacyl-tRNA synthetases GltX and TrpS. The stringent response regulator SpoT is required for HipA-mediated antibiotic persistence, but persister cells can form in the absence of all hipBA operons or spoT, indicating that multiple pathways lead to persister cell formation in C. crescentus.

2020-02-06 | PXD015525 | Pride

Expression profile for overproduction of ArT

2014-05-13 | E-GEOD-54271 | biostudies-arrayexpress

MALDI mass spectrometry imaging of c-di-GMP in bacterial biofilms

Project description:Bacterial biofilms of V. cholerae, V. fischeri, and P. aeruginosa grown on agar we analyzed by MALDI mass spectrometry imaging in negative mode for the detection of cyclic dimeric guanosine monophosphate (c-di-GMP). P. aeruginosa samples were also analyzed in positive mode for the detection of additional metabolites. The presence of c-di-GMP was confirmed by MALDI MSMS of a V. cholerae extract. All raw data files are provided, .imzml datafiles provided as supplementary files.

| MSV000092966 | MassIVE

Biofilm formation on human immune cells is a multicellular predation strategy of Vibrio cholerae

Project description:Biofilm formation is generally recognized as a bacterial defense mechanism against environmental threats, including antibiotics, bacteriophages, and leukocytes of the human immune system. Here, we show that for the human pathogen Vibrio cholerae, biofilm formation is not only a protective trait, but also an aggressive trait to collectively predate different types of immune cells. We find that V. cholerae forms biofilms on the eukaryotic cell surface using an extracellular matrix comprising primarily mannose-sensitive hemagglutinin pili, toxin-coregulated pili, and the secreted colonization factor TcpF, which is distinct from the matrix composition of biofilms on abiotic surfaces. These biofilms encase immune cells and establish a high local concentration of a secreted hemolysin to kill the immune cells, before the biofilms disperse in a c-di-GMP-dependent manner. Together, these results uncover a mechanism for how bacteria employ biofilm formation as a multicellular strategy to invert the typical relationship between the human immune system as the hunter and bacteria as the hunted.

2023-05-25 | PXD039577 | Pride

Biofilm formation on human immune cells is a multicellular predation strategy of Vibrio cholerae

2023-05-25 | PXD039579 | Pride

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