ParST is a widespread toxin–antitoxin module that targets nucleotide metabolism

Piscotta, Frank J.; Jeffrey, Philip D.; Link, A. James

doi:10.1073/pnas.1814633116

Cited by 25 publications

(36 citation statements)

References 64 publications

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“…Finally, SNPs in genes coding for a toxin-antitoxin system ( PA1029 - PA1030 ) and cell metabolism ( coaD) were associated with increased tolerance. PA1030 encodes a toxin of the RES domain family that was recently shown to interfere with NAD metabolism 35–37 .…”

Section: Resultsmentioning

confidence: 99%

Evolution of Antibiotic Tolerance Shapes Resistance Development in ChronicPseudomonas aeruginosaInfections

Santi

Manfredi²,

Maffei³

et al. 2020

Preprint

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The widespread use of antibiotics promotes the evolution and dissemination of resistance and tolerance mechanisms. To assess the relevance of tolerance and its implications for resistance development, we used in vitro evolution and analyzed in-patient microevolution of Pseudomonas aeruginosa, an important human pathogen causing acute and chronic infections. We show that the development of tolerance precedes and promotes the acquisition of resistance in vitro and we present evidence that similar processes shape antibiotic exposure in human patients. Our data suggest that during chronic infections, P. aeruginosa first acquires moderate drug tolerance before following distinct evolutionary trajectories that lead to high-level multi-drug tolerance or to antibiotic resistance. Our studies propose that the development of antibiotic tolerance predisposes bacteria for the acquisition of resistance at early stages of infection and that both mechanisms independently promote bacterial survival during antibiotic treatment at later stages of chronic infections.

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Section: Resultsmentioning

confidence: 99%

Evolution of Antibiotic Tolerance Shapes Resistance Development in ChronicPseudomonas aeruginosaInfections

Santi

Manfredi²,

Maffei³

et al. 2020

Preprint

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“…The Streptococcus pneumoniae chromosomal PezAT system, a xenolog of the Epsilon-Zeta system [108], is located within an integrated pathogenicity island, and when deleted induced phenotypic changes that produced both beneficial (harder to lyse) and negative (more sensitive to cell wall antibiotics) effects for the cell [109]. The ParST, an mART-type that transfers an ADP-ribosyl group onto an enzyme involved in phosphoribosyl pyrophosphate synthetase, induces bacteriostasis when transplanted from its native Sphingobium host to E. coli [110]. This study notes the widespread distribution of the ParST system with enrichment in Proteobacterial classes.…”

Section: Functions Attributed To Chromosomal Type II Ta Systemsmentioning

confidence: 99%

Evaluating the Potential for Cross-Interactions of Antitoxins in Type II TA Systems

Holt

Ruan

2020

Toxins

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The diversity of Type-II toxin–antitoxin (TA) systems in bacterial genomes requires tightly controlled interaction specificity to ensure protection of the cell, and potentially to limit cross-talk between toxin–antitoxin pairs of the same family of TA systems. Further, there is a redundant use of toxin folds for different cellular targets and complexation with different classes of antitoxins, increasing the apparent requirement for the insulation of interactions. The presence of Type II TA systems has remained enigmatic with respect to potential benefits imparted to the host cells. In some cases, they play clear roles in survival associated with unfavorable growth conditions. More generally, they can also serve as a “cure” against acquisition of highly similar TA systems such as those found on plasmids or invading genetic elements that frequently carry virulence and resistance genes. The latter model is predicated on the ability of these highly specific cognate antitoxin–toxin interactions to form cross-reactions between chromosomal antitoxins and invading toxins. This review summarizes advances in the Type II TA system models with an emphasis on antitoxin cross-reactivity, including with invading genetic elements and cases where toxin proteins share a common fold yet interact with different families of antitoxins.

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“…Additional TA systems involving ADPr encompasses ParST encoded by the bacterium Sphingobium sp. YBL2 [267]. ParT exerts bacteriostatic effects via ADPr of phosphoribosyl pyrophosphate synthetase (Prs), an essential enzyme in nucleotide biosynthesis conserved in all organisms.…”

Section: Endogenous Bacterial Adpr and Cell Homeostasis Regulationmentioning

confidence: 99%

Targeting ADP-ribosylation as an antimicrobial strategy

Catara

Corteggio

Valente

et al. 2019

Biochemical Pharmacology

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A B S T R A C T ADP-ribosylation (ADPr) is an ancient reversible modification of cellular macromolecules controlling major biological processes as diverse as DNA damage repair, transcriptional regulation, intracellular transport, immune and stress responses, cell survival and proliferation. Furthermore, enzymatic reactions of ADPr are central in the pathogenesis of many human diseases, including infectious conditions. By providing a review of ADPr signalling in bacterial systems, we highlight the relevance of this chemical modification in the pathogenesis of human diseases depending on host-pathogen interactions. The post-antibiotic era has raised the need to find alternative approaches to antibiotic administration, as major pathogens becoming resistant to antibiotics. An in-depth understanding of ADPr reactions provides the rationale for designing novel antimicrobial strategies for treatment of infectious diseases. In addition, the understanding of mechanisms of ADPr by bacterial virulence factors offers important hints to improve our knowledge on cellular processes regulated by eukaryotic homologous enzymes, which are often involved in the pathogenesis of human diseases.T large number of worldwide spread diseases, affecting humans, insects and plants [31,[56][57][58], with a great impact on human health. In addition, infectious diseases strongly affect the world economy in terms of costs for the human health as well as food and agricultural economic losses [59]. The use of antibiotics to counteract the pathogen infections has represented the therapeutic strategy of choice in the last century, however the emergence of antibiotic resistance strains represents the major challenge of the 21st century [60][61][62]. Targeting bacterial pathogenic mechanisms by disarming pathogens of virulence factors, for instance by inhibiting the enzymatic activity of bART, represents a valid alternative intervention strategy to overcome antibiotic resistance [63][64][65][66]. In addition, because of the conservation of ADPr systems throughout the evolution, the understanding of bacterial pathogenic mechanisms may contribute to unveil novel and conserved cellular processes regulated by ADPr in high organisms [34,45,67,68]. The dysregulation of such processes can be either cause of human diseases or be target of therapeutic intervention [39,[69][70][71].Herein, we will provide a summary of bacterial ADPr systems describing their pathogenic mechanisms and highlighting the similarities with ADPr systems in mammals as well. Further, we discuss the potential of targeting ADPr for therapeutic strategies of infection diseases. ADP-ribosylation in pathophysiologyADPr was originally described in the 60s; two independent studies reported the identification of a new polymer, poly(ADP-ribose) (PAR) synthesised from NAD + in vertebrate cells [72] and, simultaneously, the finding that bacterial DTX activity from C. diphteriae is dependent on NAD + content [73]. In the following decades, research in the field has expanded the involvement of ADPr ...

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ParST is a widespread toxin–antitoxin module that targets nucleotide metabolism

Cited by 25 publications

References 64 publications

Evolution of Antibiotic Tolerance Shapes Resistance Development in ChronicPseudomonas aeruginosaInfections

Evolution of Antibiotic Tolerance Shapes Resistance Development in ChronicPseudomonas aeruginosaInfections

Evaluating the Potential for Cross-Interactions of Antitoxins in Type II TA Systems

Targeting ADP-ribosylation as an antimicrobial strategy

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