MazF toxin causes alterations in <i>Staphylococcus aureus</i> transcriptome, translatome and proteome that underlie bacterial dormancy

Bezrukov, Fedor; Prados, Julien; Renzoni, Adriana; Panasenko, Olesya O.

doi:10.1093/nar/gkaa1292

Cited by 17 publications

(7 citation statements)

References 65 publications

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“…These include maintenance of redox homeostasis (5 oxidoreductases, SERP2129, SERP1917, SERP2165, SERP0244 and nfrA, were significantly reduced at N57), betaine membrane transport (SERP0246 and SERP2179), insertion of integral membrane proteins (SERP1356) and adjustment of the cell-wall protein composition (SERP2279, sdrH, gtf1). Interestingly, an endoribonuclease from the type II toxin-antitoxin system, MasF, only decreased at N57 relative to N55, was described as an inducer of bacterial dormancy ( Bezrukov et al, 2021 ). Several processes were triggered at N57, most of them also incremented at N77 when compared to N55, such as metabolism of acetoin, PTS, pyruvate fermentation, transmembrane transport (including of hemin), and biosynthesis of purines, TCS, extracellular proteases.…”

Section: Resultsmentioning

confidence: 99%

Skin-to-blood pH shift triggers metabolome and proteome global remodelling in Staphylococcus epidermidis

et al. 2022

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Staphylococcus epidermidis is one of the most common bacteria of the human skin microbiota. Despite its role as a commensal, S. epidermidis has emerged as an opportunistic pathogen, associated with 80% of medical devices related infections. Moreover, these bacteria are extremely difficult to treat due to their ability to form biofilms and accumulate resistance to almost all classes of antimicrobials. Thus new preventive and therapeutic strategies are urgently needed. However, the molecular mechanisms associated with S. epidermidis colonisation and disease are still poorly understood. A deeper understanding of the metabolic and cellular processes associated with response to environmental factors characteristic of SE ecological niches in health and disease might provide new clues on colonisation and disease processes. Here we studied the impact of pH conditions, mimicking the skin pH (5.5) and blood pH (7.4), in a S. epidermidis commensal strain by means of next-generation proteomics and 1H NMR-based metabolomics. Moreover, we evaluated the metabolic changes occurring during a sudden pH change, simulating the skin barrier break produced by a catheter. We found that exposure of S. epidermidis to skin pH induced oxidative phosphorylation and biosynthesis of peptidoglycan, lipoteichoic acids and betaine. In contrast, at blood pH, the bacterial assimilation of monosaccharides and its oxidation by glycolysis and fermentation was promoted. Additionally, several proteins related to virulence and immune evasion, namely extracellular proteases and membrane iron transporters were more abundant at blood pH. In the situation of an abrupt skin-to-blood pH shift we observed the decrease in the osmolyte betaine and changes in the levels of several metabolites and proteins involved in cellular redoxl homeostasis. Our results suggest that at the skin pH S. epidermidis cells are metabolically more active and adhesion is promoted, while at blood pH, metabolism is tuned down and cells have a more virulent profile. pH increase during commensal-to-pathogen conversion appears to be a critical environmental signal to the remodelling of the S. epidermidis metabolism toward a more pathogenic state. Targeting S. epidermidis proteins induced by pH 7.4 and promoting the acidification of the medical device surface or surrounding environment might be new strategies to treat and prevent S. epidermidis infections.

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Section: Resultsmentioning

confidence: 99%

Skin-to-blood pH shift triggers metabolome and proteome global remodelling in Staphylococcus epidermidis

et al. 2022

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“…Recently, a MazEF homolog (MazF-dr) in Deinococcus radiodurans responds by an increase in ROS accumulation upon DNA damage stress [27]. Moreover, MazF in Staphylococcus aureus may contribute to reversible bacteria dormancy through activation of translation rescue, ribosome hibernation, the increase of cell wall thickness, and the decrease of cell division [28].…”

Section: Discussionmentioning

confidence: 99%

Functional Characterization of the mazEF Toxin-Antitoxin System in the Pathogenic Bacterium Agrobacterium tumefaciens

et al. 2021

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Agrobacterium tumefaciens is a pathogen of various plants which transfers its own DNA (T-DNA) to the host plants. It is used for producing genetically modified plants with this ability. To control T-DNA transfer to the right place, toxin-antitoxin (TA) systems of A. tumefaciens were used to control the target site of transfer without any unintentional targeting. Here, we describe a toxin-antitoxin system, Atu0939 (mazE-at) and Atu0940 (mazF-at), in the chromosome of Agrobacterium tumefaciens. The toxin in the TA system has 33.3% identity and 45.5% similarity with MazF in Escherichia coli. The expression of MazF-at caused cell growth inhibition, while cells with MazF-at co-expressed with MazE-at grew normally. In vivo and in vitro assays revealed that MazF-at inhibited protein synthesis by decreasing the cellular mRNA stability. Moreover, the catalytic residue of MazF-at was determined to be the 24th glutamic acid using site-directed mutagenesis. From the results, we concluded that MazF-at is a type II toxin-antitoxin system and a ribosome-independent endoribonuclease. Here, we characterized a TA system in A. tumefaciens whose understanding might help to find its physiological function and to develop further applications.

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“…15,16 In Staphylococcus aureus, MazF recognizes and cleaves mRNA at UACAU, causing a global change in the transcriptome, translatome, and proteome, resulting in bacterial dormancy and antibiotic resistance. [17][18][19] In Nitrosomonas europaea, MazF specifically recognizes and cleaves at UGG trinucleotide and specifically, and two transcripts: hydroxylamine dehydrogenase (hao) and a large subunit of ribulose 1,5-bisphosphate carboxylase/oxygenase (rbcL), are among its targets. 20 MazF of Methanohalobium evestigatum specifically cleaves mRNA at CUGGU/UUGGU.…”

Section: Introductionmentioning

confidence: 99%

“…In addition to their mRNA endonuclease activity, MazF‐mt3 cleaves 16S and 23S rRNA; MazF‐mt6 specifically recognize UU^CCU and cleaves the 23S rRNA helix 70 in the ribosomal A site (^ indicates cleavage site), thus inhibiting translation 13,14 ; MazF‐mt9 recognize tRNA Lys and cleaves at UUU of the anticodon loop, regardless the sequences outside of the loop 15,16 . In Staphylococcus aureus , MazF recognizes and cleaves mRNA at UACAU, causing a global change in the transcriptome, translatome, and proteome, resulting in bacterial dormancy and antibiotic resistance 17–19 . In Nitrosomonas europaea , MazF specifically recognizes and cleaves at UGG trinucleotide and specifically, and two transcripts: hydroxylamine dehydrogenase ( hao ) and a large subunit of ribulose 1,5‐bisphosphate carboxylase/oxygenase ( rbcL ), are among its targets 20 .…”

Section: Introductionmentioning

confidence: 99%

Helicobacter macacaeMazF interplays with Escherichia coli homologs and enhances antibiotic tolerance

Zeng

et al. 2023

Helicobacter

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BackgroundToxin‐antitoxin systems are highly variable, even among strains of the same bacterial species. The MazEF toxin‐antitoxin system is found in many bacteria and plays important roles in various biological processes such as antibiotic tolerance and phage defense. However, no interplay of MazEF systems between different species was reported.Materials and MethodsMazEF toxin‐antitoxin system of Helicobacter macacae was examined in three Escherichia coli strains with and without endogenous MazEF knockout. In vivo toxicity, antibiotic tolerance, and live/dead staining followed by flowcytometry analysis were performed to evaluate the functionality and interplay of the toxin‐antitoxin system between the two species.ResultsControlled ectopic expression of MazF of H. macacae (MazFhm) in E. coli did not affect its growth. However, in endogenous MazEF knockout E. coli strains, MazFhm expression caused a sharp growth arrest. The toxicity of MazFhm could be neutralized by both the antitoxin of MazE homolog of H.macacae and the antitoxin of MazE of E. coli, indicating interplay of MazEF toxin‐antitoxin systems between the two species. Induced expression of MazFhm enhanced tolerance to a lethal dose of levofloxacin, suggesting enhanced persister formation, which was further confirmed by live/dead cell staining.ConclusionsThe MazEF toxin‐antitoxin system of H. macace enhances persister formation and thus antibiotic tolerance in E. coli. Our findings reveal an interplay between the MazEF systems of H. macacae and E. coli, emphasizing the need to consider this interaction while evaluating the toxicity and functionality of MazF homologs from different species in future studies.

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MazF toxin causes alterations in Staphylococcus aureus transcriptome, translatome and proteome that underlie bacterial dormancy

Cited by 17 publications

References 65 publications

Skin-to-blood pH shift triggers metabolome and proteome global remodelling in Staphylococcus epidermidis

Skin-to-blood pH shift triggers metabolome and proteome global remodelling in Staphylococcus epidermidis

Functional Characterization of the mazEF Toxin-Antitoxin System in the Pathogenic Bacterium Agrobacterium tumefaciens

Helicobacter macacaeMazF interplays with Escherichia coli homologs and enhances antibiotic tolerance

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