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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]

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Project description:Many bacteria are often resistant to antibiotic treatment and drugs because, even if these drugs are effective, bacteria can slow down their growth rate and thus attenuate the effectiveness of the drug. A similar growth-rate control is detected in pathogenic bacteria that infect and persist inside their hosts. The bacterial growth rate within host cells can be regulated by multiple signaling pathways, most of which are still unknown. A toxin-antitoxin (TA) system is one of the candidates for controlling bacterial growth because the TA system could slow down growth by expressing a toxin component. The toxin protein can be neutralized by the antitoxin component, serving as a non-heritable phenotypic switch for growth rate. In this study, we investigated a type II toxin-antitoxin system from the intracellular bacterial pathogen Salmonella enterica serovar Typhimurium. We characterized residues required for toxin’s activity and a potential mechanism of the toxin by searching for its target via bacterial two-hybrid screening. Understanding the underlying mechanism of toxin-mediated persister formation and growth rate control within host cells will provide a new alternative to treat antibiotic resistant bacteria or intracellular bacteria surviving within host cells.

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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.

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Expression profile for overproduction of ArT

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| MSV000092966 | MassIVE

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