The alarmones (p)ppGpp directly regulate translation initiation during entry into quiescence

Diez, Simon; Ryu, Jae-Wook; Caban, Kelvin; Gonzalez, Ruben L; Dworkin, Jonathan

doi:10.1073/pnas.1920013117

Cited by 72 publications

(96 citation statements)

References 71 publications

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“…Our findings are supported by a recent report showing that (p)ppGpp inhibits the activation of IF2 leading to the attenuation of initiation of translation during the switch from active growth to quiescence in the Gram-positive bacterium Bacillus subtilis (19).…”

Section: Resultssupporting

confidence: 90%

The generation of persister cells is regulated at the initiation of translation by (p)ppGpp

Molina-Quiroz

Camilli

2020

Preprint

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Bacterial persistence is a non-heritable phenotypic trait characterized by a dormant state that leads to tolerance to different antibiotics. Several mechanisms contributing to persister cells generation have been identified. Among these, is the signaling molecule (p)ppGpp, but knowledge of how this molecule regulates persister generation is incomplete. Here, we show an increase of the persister fraction of uropathogenic Escherichia coli (UPEC) that correlates with the time of protein synthesis inhibition and a decrease in the availability of antibiotic target. Specifically, the arrest of translation initiation induces bacterial survival to ampicillin and ciprofloxacin in a (p)ppGpp-dependent manner. These findings support a global mechanism of persister cell generation and establish a regulatory role of the (p)ppGpp molecule in this phenomenon.ImportanceThe study of persister cell formation is relevant because this bacterial subpopulation is involved in the emergence of antibiotic resistance and the generation of chronic infections. A role of the (p)ppGpp molecule in the generation of the persister fraction has been described, but the identification of the regulatory mechanism mediated by this alarmone during protein translation and its contribution to persistence has not been described to date. In this work, we show that (p)ppGpp regulates the generation of persister cells at the initiation of the protein synthesis process in UPEC. Our results also suggest that a (p)ppGpp-dependent regulation of translation, might be a global mechanism for the generation of the persister fraction.

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Section: Resultssupporting

confidence: 90%

The generation of persister cells is regulated at the initiation of translation by (p)ppGpp

Molina-Quiroz

Camilli

2020

Preprint

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“…Compared to the many targets discovered for (p)ppGpp in Gram-negative bacteria, little is known about (p)ppGpp targets in Gram-positive firmicutes. In many bacteria, GTPases can be competitively inhibited by (p)ppGpp, including the ribosomal translation factors EF-Tu, EF-G, RF3 and IF2 [ 28 , [36] , [37] , [38] , [39] ]. In S. aureus , (p)ppGpp was shown to inhibit two enzymes needed for GTP synthesis (HprT and Gmk) and five GTPases (RsgA, RbgA, Era, HflX and ObgE) that are implicated in ribosome assembly [ 40 , 41 ].…”

Section: Introductionmentioning

confidence: 99%

The alarmone (p)ppGpp confers tolerance to oxidative stress during the stationary phase by maintenance of redox and iron homeostasis in Staphylococcus aureus

Fritsch

Loi

Busche

et al. 2020

Free Radical Biology and Medicine

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Slow growing stationary phase bacteria are often tolerant to multiple stressors and antimicrobials. Here, we show that the pathogen Staphylococcus aureus develops a non-specific tolerance towards oxidative stress during the stationary phase, which is mediated by the nucleotide second messenger (p)ppGpp. The (p)ppGpp 0 mutant was highly susceptible to HOCl stress during the stationary phase. Transcriptome analysis of the (p)ppGpp 0 mutant revealed an increased expression of the PerR, SigB, QsrR, CtsR and HrcA regulons during the stationary phase, indicating an oxidative stress response. The (p)ppGpp 0 mutant showed a slight oxidative shift in the bacillithiol (BSH) redox potential ( E BSH ) and an impaired H 2 O 2 detoxification due to higher endogenous ROS levels. The increased ROS levels in the (p)ppGpp 0 mutant were shown to be caused by higher respiratory chain activity and elevated total and free iron levels. Consistent with these results, N-acetyl cysteine and the iron-chelator dipyridyl improved the growth and survival of the (p)ppGpp 0 mutant under oxidative stress. Elevated free iron levels caused 8 to 31-fold increased transcription of Fe-storage proteins ferritin ( ftnA ) and miniferritin ( dps ) in the (p)ppGpp 0 mutant, while Fur-regulated uptake systems for iron, heme or siderophores ( efeOBU , isdABCDEFG , sirABC and sstADBCD ) were repressed. Finally, the susceptibility of the (p)ppGpp 0 mutant towards the bactericidal action of the antibiotics ciprofloxacin and tetracycline was abrogated with N-acetyl cysteine and dipyridyl. Taken together, (p)ppGpp confers tolerance to ROS and antibiotics by down-regulation of respiratory chain activity and free iron levels, lowering ROS formation to ensure redox homeostasis in S. aureus .

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“…Selective inhibition by ppGpp of the initiation functions of IF2, such as 30SIC formation and docking of the 50S subunit to yield a 70SIC, was confirmed in a recent study in which it was shown that inhibition of IF2 activity by ppGpp occurs also during cellular entry into quiescence ( Diez et al, 2020 ).…”

Section: Introductionmentioning

confidence: 70%

The Ribosome as a Switchboard for Bacterial Stress Response

Gualerzi

2021

Front. Microbiol.

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As free-living organisms, bacteria are subject to continuous, numerous and occasionally drastic environmental changes to which they respond with various mechanisms which enable them to adapt to the new conditions so as to survive. Here we describe three situations in which the ribosome and its functions represent the sensor or the target of the stress and play a key role in the subsequent cellular response. The three stress conditions which are described are those ensuing upon: a) zinc starvation; b) nutritional deprivation, and c) temperature downshift.

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The alarmones (p)ppGpp directly regulate translation initiation during entry into quiescence

Cited by 72 publications

References 71 publications

The generation of persister cells is regulated at the initiation of translation by (p)ppGpp

The generation of persister cells is regulated at the initiation of translation by (p)ppGpp

The alarmone (p)ppGpp confers tolerance to oxidative stress during the stationary phase by maintenance of redox and iron homeostasis in Staphylococcus aureus

The Ribosome as a Switchboard for Bacterial Stress Response

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