The expression of type II TA system genes following persister cell formation in Pseudomonas aeruginosa isolates in the exponential and stationary phases

Zadeh, Rezvan Golmoradi; Mirshekar, Maryam; Kalani, Behrooz Sadeghi; Pourghader, Johar; Barati, Mahmood; Jazi, Faramarz Masjedian

doi:10.1007/s00203-022-03038-x

Cited by 9 publications

(7 citation statements)

References 27 publications

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“…However, only four of these, including NatT, are part of the core genome 53 . Similar to other RES domain toxins 12 , natT expression is induced by different stressors, including redox stress, antibiotics or in media mimicking host conditions [28][29][30] . Moreover, a P. aeruginosa natT mutant was recently shown to be more susceptible to killing by different classes of bactericidal antibiotics and to promote survival in macrophages 30 .…”

Section: Discussionmentioning

confidence: 99%

“…E.g., the MbcA-MbcT system of M. tuberculosis is significantly upregulated in a variety of stress conditions, including persister cells 23 , hypoxic stress 24 , starvation 25 , and in human macrophages 26,27 . Similarly, the natR-natT module of P. aeruginosa is induced under oxidative stress conditions, exposure to antibiotics and under host-like conditions [28][29][30] and natT mutants show reduced survival during antibiotic treatment and in macrophages 30 . While this indicated that RES-domain TA systems are involved in cellular homeostasis and stress response, the mechanisms controlling their activity remain unknown.…”

Section: Introductionmentioning

confidence: 99%

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Toxin-mediated depletion of nicotinamide dinucleotides drives persister formation in a human pathogen

Santi,

Dias Teixeira,

Manfredi

et al. 2023

Preprint

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Toxin-antitoxin (TA) systems are widespread in bacteria and are implicated in genome stability, virulence, phage defense and persistence. Although TA systems encompass a large variety of molecular activities and cellular targets, their physiological role and regulatory mechanisms are often unclear1,2. Here, we show that a RES domain TA system increases the survival of the human pathogenP. aeruginosaduring antibiotic treatment by generating a subpopulation of highly drug-tolerant persisters. The NatT toxin is an NAD phosphorylase, which leads to strong depletion of NAD and NADP in a subpopulation of cells. Actively growingP. aeruginosacells effectively compensate for toxin-mediated NAD deficiency by inducing the NAD salvage path-way. In contrast, under nutrient-limited conditions, NatT generates NAD-depleted cells that give rise to drug tolerant persisters during outgrowth. Structural and biochemical analyses of active and inactive NatR-NatT complexes reveal how changes in NatR-NatT interaction controls toxin activity and autoregulation. Finally, we show that the NAD precursor nicotinamide blocks NatT activity and eliminates persister formation, exposing powerful metabolic feedback control of toxin activity. The findings that patient isolates containnatTgain-of-function alleles and that NatT increasesP. aeruginosavirulence, argue that NatT contributes toP. aeruginosafitness during infections. These studies provide mechanistic insight into how a TA system promotes pathogen persistence by disrupting essential metabolic pathways during nutrient stress.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Toxin-mediated depletion of nicotinamide dinucleotides drives persister formation in a human pathogen

Santi,

Dias Teixeira,

Manfredi

et al. 2023

Preprint

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“…relBE expression is increased in isolates that are sensitive, compared with isolates that are resistant to aztreonam [ 50 ]. Zadeh et al showed that the expression of relBE promotes persister cell formation in biofilms in the presence of ciprofloxacin and colistin in P. aeruginosa [ 52 ]. RelBE TA systems control biofilm formation by indirectly regulating the expression of biofilm-associated genes [ 36 ].…”

Section: Biological Functions Of Type II Ta Systems In P Ae...mentioning

confidence: 99%

Type II Toxin–Antitoxin Systems in Pseudomonas aeruginosa

Guo

Song

et al. 2023

Toxins

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Toxin–antitoxin (TA) systems are typically composed of a stable toxin and a labile antitoxin; the latter counteracts the toxicity of the former under suitable conditions. TA systems are classified into eight types based on the nature and molecular modes of action of the antitoxin component so far. The 10 pairs of TA systems discovered and experimentally characterised in Pseudomonas aeruginosa are type II TA systems. Type II TA systems have various physiological functions, such as virulence and biofilm formation, protection host against antibiotics, persistence, plasmid maintenance, and prophage production. Here, we review the type II TA systems of P. aeruginosa, focusing on their biological functions and regulatory mechanisms, providing potential applications for the novel drug design.

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“…According to the TADB 2.0 database, five pairs of type II TA cassettes have been identified in the P. aeruginosa PAO1 genome: PA0124/PA0123 (denoted as ParDE, par operon in the RK2 plasmid), PA4674.1/PA4674 (denoted as HigBA, host inhibition of growth), PA1030/PA1029, PA1878/PA1879, and PA3270/PA3269 ( Xie et al., 2018 ). The increase in their expression levels were associated with ciprofloxacin- and colistin-induced persister cell formation by P. aeruginosa isolates ( Golmoradi Zadeh et al., 2022 ). The toxin ParE protects P. aeruginosa against the quinolone and other antibiotics by inhibiting gyrase-mediated DNA supercoiling, while higher ParE concentrations are also themselves toxic to cells ( Muthuramalingam et al., 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Comparative analysis of five type II TA systems identified in Pseudomonas aeruginosa reveals their contributions to persistence and intracellular survival

Song

Hong

Bao

2023

Front. Cell. Infect. Microbiol.

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BackgroundPseudomonas aeruginosa is a grave nosocomial pathogen that persistently inhabits the lungs of patients with cystic fibrosis (CF) and causes various chronic infections. The bacterial toxin–antitoxin (TA) system is associated with latent and long-term infections, but the underlying mechanisms remain to be fully characterized.MethodsWe here investigated the diversity and function of five genomic type II TA systems widely distributed among P. aeruginosa clinical isolates. We also examined the distinct structural features of the toxin protein from different TA systems and characterized their contributions to persistence, invasion ability, and intracellular infection caused by P. aeruginosa.ResultsParDE, PA1030/PA1029, and HigBA could modulate persister cell formation under treatment with specific antibiotics. Furthermore, cell-based transcriptional and invasion assays revealed that PA1030/PA1029 and HigBA TA systems were critical for intracellular survival.DiscussionOur results highlight the prevalence and diverse roles of type II TA systems in P. aeruginosa and evaluate the possibility of using PA1030/PA1029 and HigBA TA pairs as targets for novel antibiotic treatments.

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The expression of type II TA system genes following persister cell formation in Pseudomonas aeruginosa isolates in the exponential and stationary phases

Cited by 9 publications

References 27 publications

Toxin-mediated depletion of nicotinamide dinucleotides drives persister formation in a human pathogen

Toxin-mediated depletion of nicotinamide dinucleotides drives persister formation in a human pathogen

Type II Toxin–Antitoxin Systems in Pseudomonas aeruginosa

Comparative analysis of five type II TA systems identified in Pseudomonas aeruginosa reveals their contributions to persistence and intracellular survival

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