Stress Can Induce Transcription of Toxin-Antitoxin Systems without Activating Toxin

LeRoux, Michele; Culviner, Peter H.; Liu, Yue J.; Littlehale, Megan L; Laub, Michael T.

doi:10.1016/j.molcel.2020.05.028

Cited by 95 publications

(124 citation statements)

References 69 publications

(97 reference statements)

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“…For example, isoleucine starvation of E. coli increases (p)ppGpp levels and leads to an upregulation of many type II TA modules, like MazEF, HicAB, RelBE and MqsRA as well as the type I toxin HokB (Fig. 2) (Traxler et al , 2008; Verstraeten et al , 2015; Shan et al , 2017; LeRoux et al , 2020). Mutations that affect (p)ppGpp synthesis significantly reduce persister levels in both Gram‐positive and Gram‐negative bacteria, indicating the prominent role and connections of stringent response with bacterial stress response and antibiotic persistence (Amato et al , 2013; Amato et al , 2014).…”

Section: The Antibiotic Resistance Crisismentioning

confidence: 99%

Antibiotic resistance and persistence—Implications for human health and treatment perspectives

et al. 2020

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Antimicrobial resistance (AMR) and persistence are associated with an elevated risk of treatment failure and relapsing infections. They are thus important drivers of increased morbidity and mortality rates resulting in growing healthcare costs. Antibiotic resistance is readily identifiable with standard microbiological assays, and the threat imposed by antibiotic resistance has been well recognized. Measures aiming to reduce resistance development and spreading of resistant bacteria are being enforced. However, the phenomenon of bacteria surviving antibiotic exposure despite being fully susceptible, so‐called antibiotic persistence, is still largely underestimated. In contrast to antibiotic resistance, antibiotic persistence is difficult to measure and therefore often missed, potentially leading to treatment failures. In this review, we focus on bacterial mechanisms allowing evasion of antibiotic killing and discuss their implications on human health. We describe the relationship between antibiotic persistence and bacterial heterogeneity and discuss recent studies that link bacterial persistence and tolerance with the evolution of antibiotic resistance. Finally, we review persister detection methods, novel strategies aiming at eradicating bacterial persisters and the latest advances in the development of new antibiotics.

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Section: The Antibiotic Resistance Crisismentioning

confidence: 99%

Antibiotic resistance and persistence—Implications for human health and treatment perspectives

et al. 2020

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“…Moreover, MqsR/MqsA affects biofilm formation in Pseudomonas fluorescens ( Wang et al, 2019 ) and persistence and biofilm formation in Pseudomonas putida ( Sun et al, 2017 ). Similarly, other TA systems such as the MazE/MazF ( Kolodkin-Gal et al, 2007 ), RelE/RelB ( Christensen et al, 2001 ), and YafQ/DinJ ( Zhao et al, 2016 ) TA systems have been linked to the general stress response; but their roles have also been disputed in E. coli ( LeRoux et al, 2020a ).…”

Section: Toxin/antitoxin Systems and The General Stress Responsementioning

confidence: 99%

A Primary Physiological Role of Toxin/Antitoxin Systems Is Phage Inhibition

2020

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Toxin/antitoxin (TA) systems are present in most prokaryote genomes. Toxins are almost exclusively proteins that reduce metabolism (but do not cause cell death), and antitoxins are either RNA or proteins that counteract the toxin or the RNA that encodes it. Although TA systems clearly stabilize mobile genetic elements, after four decades of research, the physiological roles of chromosomal TA systems are less clear. For example, recent reports have challenged the notion of TA systems as stress-response elements, including a role in creating the dormant state known as persistence. Here, we present evidence that a primary physiological role of chromosomally encoded TA systems is phage inhibition, a role that is also played by some plasmid-based TA systems. This includes results that show some CRISPR-Cas system elements are derived from TA systems and that some CRISPR-Cas systems mimic the host growth inhibition invoked by TA systems to inhibit phage propagation.

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“…However, it is also important not to infer too much from studies of mutant strains about the physiological roles of these proteins in wild type cells. A criticism which is often levelled at studies of TA systems is that phenotypes of antitoxin mutant strains are not equivalent to phenotypes of wild type cells experiencing high levels of toxin production and therefore not physiologically relevant (2,19,21), and therefore a phenotype associated with a given TA system should only be postulated if a phenotype can be observed for a toxin or whole TA system mutant. We do indeed observe such a phenotype for HigBA, since the loss of the toxin in the ΔlexA background substantially improved its resistance to ciprofloxacin.…”

Section: Discussionmentioning

confidence: 99%

“…Another study which showed that the type II TA system MqsRA of E. coli was an important mediator of the stress response (17) could not be reproduced by other groups (18). Frequently it has been assumed that the transcriptional activation of TA systems in response to various stress conditions is an indication that they are important for the corresponding stress response, and that transcriptional activation could be used as a proxy for activation of the TA system at the functional level, but it has recently been shown that during transcriptional activation of the stress-induced type II TA systems in E. coli, their toxins are neither released nor active (19). Hence, it is currently unclear whether type II TA systems have any involvement in persistence at all.…”

Section: Introductionmentioning

confidence: 99%

A toxin-antitoxin system associated transcription factor of Caulobacter crescentus can influence cell cycle-regulated gene expression during the SOS response

Ghosh

Brejndal

Kirkpatrick

2020

Preprint

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Toxin-antitoxin (TA) systems are widespread in bacterial chromosomes but their functions remain enigmatic. Although many are transcriptionally upregulated by stress conditions, it is unclear what role they play in cellular responses to stress and to what extent the role of a given TA system homologue varies between different bacterial species. In this work we investigate the role of the DNA damage-inducible TA system HigBA of Caulobacter crescentus in the SOS response and discover that in addition to the toxin HigB affecting cell cycle gene expression through inhibition of the master regulator CtrA, HigBA possesses a transcription factor third component, HigC, which both auto-regulates the TA system and acts independently of it. Through HigC, the system exerts downstream effects on antibiotic (ciprofloxacin) resistance and cell cycle gene expression. HigB and HigC had inverse effects on cell cycle gene regulation, with HigB reducing and HigC increasing the expression of CtrA-dependent promoters. Neither HigBA nor HigC had any effect on formation of persister cells in response to ciprofloxacin. Rather, their role in the SOS response appears to be as transcriptional and post-transcriptional regulators of cell cycle-dependent gene expression, transmitting the status of the SOS response as a regulatory input into the cell cycle control network via CtrA.ImportanceAlmost all bacteria respond to DNA damage by upregulating a set of genes that helps them to repair and recover from the damage, known as the SOS response. The set of genes induced during the SOS response varies between species, but frequently includes toxin-antitoxin systems. However, it is unknown what the consequence of inducing these systems is, and whether they provide any benefit to the cells. We show here that the DNA damage-induced TA system HigBA of the asymmetrically dividing bacterium Caulobacter crescentus affects the cell cycle regulation of this bacterium. HigBA also has a transcription factor encoded immediately downstream of it, named here HigC, which controls expression of the TA system and potentially other genes as well. Therefore, this work identifies a new role for TA systems in the DNA damage response, distinct from non-specific stress tolerance mechanisms which had been proposed previously.

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Stress Can Induce Transcription of Toxin-Antitoxin Systems without Activating Toxin

Cited by 95 publications

References 69 publications

Antibiotic resistance and persistence—Implications for human health and treatment perspectives

Antibiotic resistance and persistence—Implications for human health and treatment perspectives

A Primary Physiological Role of Toxin/Antitoxin Systems Is Phage Inhibition

A toxin-antitoxin system associated transcription factor of Caulobacter crescentus can influence cell cycle-regulated gene expression during the SOS response

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